Substituted heterocyclic compounds, method of preparing them and pharmaceutical compositions in which they are present

ABSTRACT

The invention relates to compounds of the formula ##STR1## in which: A is a divalent radical selected from: 
     A 1 ) --O--CO-- 
     A 2 ) --CH 2  --O--CO-- 
     A 3 ) --O--CH 2  --CO-- 
     A 4 ) --O--CH 2  --CH 2  -- 
     A 5 ) --N(R 1 )--CO-- 
     A 6 ) --N(R 1 )--CO--CO-- 
     A 7 ) --N(R 1 )--CH 2  --CH 2  -- 
     A 8 ) --O--CH 2  -- 
     in which: 
     R 1  is a hydrogen or a (C 1  -C 4 )-alkyl; and 
     Am is a nitrogen-containing heterocycle.

This is a divisional application of U.S. application Ser. No. 08/820,716filed Mar. 18, 1997 now U.S. Pat. 5,869,663, which is a divisional ofU.S. application Ser. No. 08/593,938 filed on Jan. 30, 1996 which is nowU.S. Pat. No. 5,641,777.

The present invention relates to novel substituted heterocycliccompounds, to a method of preparing them and to the pharmaceuticalcompositions in which they are present as the active principle.

More particularly, the present invention relates to a novel class ofsubstituted heterocyclic compounds for therapeutic use in pathologicalphenomena involving the tachykinin system, such as: pain (D. Regoli etal., Life Sciences, 1987, 40, 109-117), allergy and inflammation (J. E.Morlay et al., Life Sciences, 1987, 41, 527-544), circulatoryinsufficiency (J. Losay et al., 1977, Substance P, Von Euler, I. S. andPernow ed., 287-293, Raven Press, New York), gastrointestinal disorders(D. Regoli et al., Trends Pharmacol. Sci., 1985, 6, 481-484),respiratory disorders (J. Mizrahi et al., Pharmacology, 1982, 25,39-50), neurological disorders and neuropsychiatric disorders (C. A.Maggi et al., J. Autonomic Pharmacol., 1993, 13, 23-93), these examplesbeing neither limiting nor exclusive.

In recent years, numerous research studies have been carried out ontachykinins and their receptors. Tachykinins are distributed throughoutboth the central nervous system and the peripheral nervous system. Thetachykinin receptors have been recognized and are classified into threetypes: NK₁, NK₂, NK₃. Substance P (SP) is the endogenous ligand of theNK₁ receptors, neurokinin A (NK_(A)) that of the NK₂ receptors andneurokinin B (NK_(B)) that of the NK₃ receptors.

The NK₁, NK₂ and NK₃ receptors have been identified in differentspecies. A review by C. A. Maggi et al. looks at the tachykininreceptors and their antagonists and gives an account of thepharmacological studies and the applications in human therapeutics (J.Autonomic Pharmacol., 1993, 13, 23-93).

The following non-peptide compounds may be mentioned among theantagonists specific for the NK₁ receptor: CP-96345 (J. Med. Chem.,1992, 35, 2591-2600), RP-68651 (Proc. Natl. Acad. Sci. USA, 1991, 88,10208-10212), SR 140333 (Curr. J. Pharmacol., 1993, 250, 403-413).

For the NK₂ receptor, a non-peptide selective antagonist, SR 48968, hasbeen described in detail (Life Sci., 1992, 50, PL101-PL106).

As far as the NK₃ receptor is concerned, some non-peptide compounds havebeen described as having an affinity for the NK₃ receptor of the rat andguinea-pig brain (FASEB J., 1993, 7 (4), A710-4104); a peptideantagonist, [Trp⁷,β-Ala⁸ ]NK_(A), which has a weak specificity for theNK₃ receptor of the rat, has also been described (J. AutonomicPharmacol., 1993, 13, 23-93).

Patent application EP-A-336230 describes peptide derivatives which aresubstance P and neurokinin A antagonists useful for the treatment andprevention of asthma.

International patent applications WO 90/05525, WO 90/05729, WO 91/09844and WO 91/18899 and European patent applications EP-A-0436334,EP-A-0429466 and EP-A-0430771 describe substance P antagonists.

European patent applications EP-A-0474561, EP-A-512901, EP-A-515240,EP-A-559538 and EP-A-591040 also relate to neurokinin receptorantagonists.

Novel substituted heterocyclic compounds have now been found which areneurokinin receptor antagonists.

Thus, according to one of its features, the present invention relates tocompounds of the formula ##STR2## in which: A is a divalent radicalselected from:

A₁) --O--CO--

A₂) --CH₂ --O--CO--

A₃) --O--CH₂ --CO--

A₄) --O--CH₂ --CH₂ --

A₅) --N(R₁)--CO--

A₆) --N(R₁)--CO--CO--

A₇) --N(R₁)--CH₂ --CH₂ --

A₈) --O--CH₂ --

in which R₁ is a hydrogen or a (C₁ -C₄)-alkyl;

m is 2 or 3;

Ar₁ is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁ -C₄)-alkoxy, a (C₁ -C₄)-alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different; athienyl which is unsubstituted or substituted by a halogen atom; abenzothienyl which is unsubstituted or substituted by a halogen atom; anaphthyl which is unsubstituted or substituted by a halogen atom; anindolyl which is unsubstituted or N-substituted by a (C₁ -C₄)-alkyl or abenzyl; an imidazolyl which is unsubstituted or substituted by a halogenatom; a pyridyl which is unsubstituted or substituted by a halogen atom;or a biphenyl;

T is a group selected from CH₂ --Z, --CH(C₆ H₅)₂ and --C(C₆ H₅)₃ ; T canalso be the group --CO--B--Z if A is a divalent radical selected from--O--CH₂ --CH₂ --, --N(R₁)--CH₂ --CH₂ -- and --O--CH₂ --;

B is a direct bond or a methylene;

Z is an optionally substituted mono-, di- or tricyclic aromatic orheteroaromatic group; and

Am is:

i--either a group Am₁ of the formula ##STR3## in which J₁ is: i₁--either a group ##STR4## in which: Ar₂ is a pyridyl; a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a hydroxyl, a (C₁ -C₄)-alkoxy, a (C₁-C₄)-alkyl, a trifluoromethyl, a nitro and a methylenedioxy, saidsubstituents being identical or different; a thienyl; a pyrimidyl; or animidazolyl which is unsubstituted or substituted by a (C₁ -C₄)-alkyl;and

R₂ is a hydrogen; a (C₁ -C₇)-alkyl; a benzyl; a formyl; or a (C₁-C₇)-alkylcarbonyl;

i₂ --or a group ##STR5## in which: Ar₂ is as defined above;

n is 0 or 1; and

R₃ is a group selected from:

(1) hydrogen;

(2) (C₁ -C₇)-alkyl;

(3) formyl;

(4) (C₁ -C₇)-alkylcarbonyl;

(5) cyano;

(6) --(CH₂)_(q) --OH;

(7) --(CH₂)_(q) --O--(C₁ -C₇)-alkyl;

(8) --(CH₂)_(q) --OCHO;

(9) --(CH₂)_(q) --OCOR₁₇ ;

(10) --(CH₂)_(q) --OCONH--(C₁ -C₇)-alkyl;

(11) --NR₄ R₅ ;

(12) --(CH₂)_(q) --NR₆ C(═W₁)R₇

(13) --(CH₂)_(q) --NR₆ COOR₈ ;

(14) --(CH₂)_(q) --NR₆ SO₂ R₉ ;

(15) --(CH₂)_(q) NR₆ C(═W₁)NR₁₀ R₁₁ ;

(16) --CH₂ --NR₁₂ R₁₃ ;

(17) --CH₂ --CH₂ --NR₁₂ R₁₃ ;

(18) --COOH;

(19) (C₁ -C₇)-alkoxycarbonyl;

(20) --C(═W₁)NR₁₀ R₁₁ ;

(21) --CH₂ --COOH;

(22) (C₁ -C₇)-alkoxycarbonylmethyl;

(23) --CH₂ --C(═W₁)NR₁₀ R₁₁ ;

(24) --O--CH₂ CH₂ --OR₁₈ ;

(25) --NR₆ COCOR₁₉ ;

(26) --CO--NR₂₀ --NR₂₁ R₂₂ ;

(27) ##STR6## (28) ##STR7## or R₃ constitutes a double bond between thecarbon atom to which it is bonded and the adjacent carbon atom of thepiperidine ring;

q is 0, 1 or 2;

W₁ is an oxygen atom or a sulfur atom;

R₄ and R₅ are each independently a hydrogen or a (C₁ -C₇)-alkyl; R₅ canalso be a (C₃ -C₇)-cycloalkylmethyl, a benzyl or a phenyl; or R₄ and R₅,together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the 4-position by a (C₁ -C₄)-alkyl;

R₆ is a hydrogen or a (C₁ -C₇)-alkyl;

R₇ is a hydrogen; a (C₁ -C₇)-alkyl; a vinyl; a phenyl; a benzyl; apyridyl; a (C₃ -C₇)-cycloalkyl which is unsubstituted or substituted byone or more methyls; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;

or R₆ and R₇ together are a group --(CH₂)_(p) --;

p is 3 or 4;

R₈ is a (C₁ -C₇)-alkyl or a phenyl;

R₉ is a (C₁ -C₇)-alkyl; an amino which is free or substituted by one ortwo (C₁ -C₇)-alkyls; or a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a (C₁ -C₇)-alkyl, a trifluoromethyl, a hydroxyl, a (C₁-C₇)-alkoxy, a carboxyl, a (C₁ -C₇)-alkoxycarbonyl, a (C₁-C₇)-alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁ -C₇)-alkyls, said substituents beingidentical or different;

R₁₀ and R₁₁ are each independently a hydrogen or a (C₁ -C₇)-alkyl; R₁₁can also be a (C₃ -C₇)-cycloalkyl, a (C₃ -C₇)-cycloalkylmethyl, ahydroxyl, a (C₁ -C₄)-alkoxy, a benzyl or a phenyl; or R₁₀ and R₁₁,together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine and perhydroazepine;

R₁₂ and R₁₃ are each independently a hydrogen or a (C₁ -C₇)-alkyl; R₁₃can also be a (C₃ -C₇)-cycloalkylmethyl or a benzyl;

R₁₇ is a (C₁ -C₇)-alkyl; a (C₃ -C₇)-cycloalkyl which is unsubstituted orsubstituted by one or more methyls; a phenyl; or a pyridyl;

R₁₈ is a hydrogen; a (C₁ -C₇)-alkyl; a formyl; or a (C₁-C₇)-alkylcarbonyl;

R₁₉ is a (C₁ -C₄)-alkoxy;

R₂₀ is a hydrogen or a (C₁ -C₇)-alkyl;

R₂₁ and R₂₂ are each independently a hydrogen or a (C₁ -C₇) -alkyl;

or alternatively R₂₁ and R₂₂, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from pyrrolidine,piperidine and morpholine;

R₂₃ is a hydrogen or a (C₁ -C₇)-alkyl; and

R₂₄ and R₂₅ are each independently a hydrogen or a (C₁ -C₇)-alkyl; R₂₅can also be a formyl or a (C₁ -C₇)-alkylcarbonyl;

i₃ --or a group ##STR8## in which: R₃ is as defined above;

R₁₄ is a (C₁ -C₇)-alkyl or a (C₃ -C₇)-cycloalkyl; R₁₄ can also be eithera group --CONR₁₅ R₁₆ if R₃ is hydrogen, or a group --NR₁₅ R₁₆ if R₃ ishydrogen, a cyano, a carboxyl, a (C₁ -C₇)-alkoxycarbonyl or a group--C(═W₁)NR₁₀ R₁₁ ; and

R₁₅ and R₁₆ are each independently a (C₁ -C₇)-alkyl; or R₁₅ and R₁₆,together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine and perhydroazepine;

ii--or a group Am₂ of the formula ##STR9## in which J₂ is: ii₁ --eithera group ##STR10## in which: Ar₃ is a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a hydroxyl, a (C₁ -C₄)-alkoxy, a (C₁ -C₄)-alkyl and atrifluoromethyl, said substituents being identical or different; and

R₂ is as defined above for J₁ ;

ii₂ --or a group ##STR11## in which: Ar₃ is as defined above;

n is 0 or 1;

Q is a (C₁ -C₆)-alkyl or a benzyl, said substituent being either in theaxial position or in the equatorial position; and

X.sup.⊖ is an anion;

iii--or a group Am₃ of the formula ##STR12## in which: Ar₂ is as definedabove;

n is 0 or 1; and

X.sup.⊖ is an anion;

iv--or a group Am₄ of the formula ##STR13## in which: Ar₂ is as definedabove;

n is 0 or 1; and

X.sup.⊖ is an anion;

and the salts thereof, where appropriate, with mineral or organic acids.

The compounds of formula (I) according to the invention also include theracemates, the optically pure isomers and the axial and equatorialisomers if Am is Am₂ in the compound of formula (I).

More particularly, the radical Z can be a phenyl group which can beunsubstituted or may contain one or more substituents.

If Z is a phenyl group, it can be monosubstituted or disubstituted,especially in the 2,4-position but also, for example, in the 2,3-, 4,5-,3,4- or 3,5-position; it can also be trisubstituted, especially in the2,4,6-position but also, for example, in the 2,3,4-, 2,3,5-, 2,4,5- or3,4,5-position, tetrasubstituted, for example in the 2,3,4,5-position,or pentasubstituted.

The radical Z can also be a bicyclic aromatic group such as 1- or2-naphthyl; or 1-, 2-, 3-, 4-, 5-, 6- or 7-indenyl in which one or morebonds can be hydrogenated, it being possible for said groups to beunsubstituted or optionally to contain one or more substituents such asthe alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, oxo,alkylcarbonylamino, alkoxycarbonyl, thioalkyl, halogen, alkoxy ortrifluoromethyl group, in which the alkyls are C₁ -C₄.

The radical Z can also be a pyridyl, thiadiazolyl, indolyl, indazolyl,imidazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl,benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl,benzisoxazolyl, benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyranyl,thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl,pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl orchromanyl group, in which one or more double bonds can be hydrogenated,it being possible for said groups to be unsubstituted or optionally tocontain one or more substituents such as the alkyl, phenyl, cyano,hydroxyalkyl, hydroxyl, alkylcarbonylamino, alkoxycarbonyl or thioalkylgroup, in which the alkyls are C₁ -C₄.

In particular, the invention relates to compounds of formula (I) inwhich:

Z is Z' and is:

a phenyl which is unsubstituted or monosubstituted or polysubstituted bya substituent selected from a halogen atom; a trifluoromethyl; a cyano;a hydroxyl; a nitro; a phenyl which is unsubstituted or monosubstitutedor polysubstituted by a halogen, a trifluoromethyl, a (C₁ -C₄)-alkyl, ahydroxyl or a (C₁ -C₄)-alkoxy, said substituents being identical ordifferent; an amino which is unsubstituted or monosubstituted orpolysubstituted by a (C₁ -C₄)-alkyl; a benzylamino; a carboxyl; a (C₁-C₁₀)-alkyl; a (C₃ -C₈)-cycloalkyl which is unsubstituted ormonosubstituted or polysubstituted by a methyl; a (C₁ -C₁₀)-alkoxy; a(C₃ -C₈)-cycloalkoxy which is unsubstituted or monosubstituted orpolysubstituted by a methyl; a mercapto; a (C₁ -C₁₀)-alkylthio; aformyloxy; a (C₁ -C₆)-alkylcarbonyloxy; a formylamino; a (C₁-C₆)-alkylcarbonylamino; a benzoylamino; a (C₁ -C₄)-alkoxycarbonyl; a(C₃ -C₇)-cycloalkoxycarbonyl; a (C₃ -C₇)-cycloalkylcarbonyl; a carbamoylwhich is unsubstituted or monosubstituted or disubstituted by a (C₁-C₄)-alkyl; a ureido which is unsubstituted or monosubstituted ordisubstituted in the 3-position by a (C₁ -C₄)-alkyl or a (C₃-C₇)-cycloalkyl; and a (pyrrolidin-1-yl)carbonylamino, said substituentsbeing identical or different;

a naphthyl which is unsubstituted or monosubstituted or polysubstitutedby a halogen, a trifluoromethyl, a (C₁ -C₄)-alkyl, a hydroxyl or a (C₁-C₄)-alkoxy; or

a pyridyl, a thienyl, an indolyl, a quinolyl, a benzothienyl or animidazolyl.

It is possible to form salts of the compounds of formula (I) other thanthe quaternary ammonium salts. These salts include those with mineraland organic acids which permit a suitable separation or crystallizationof the compounds of formula (I), such as picric acid, oxalic acid or anoptically active acid, for example a mandelic or camphosulfonic acid,and mineral and organic acids which form pharmaceutically acceptablesalts such as the hydrochloride, hydrobromide, sulfate, hydrogensulfate,dihydrogenphosphate, methanesulfonate, methylsulfate, maleate, fumarate,naphthalene-2-sulfonate, benzenesulfonate, gluconate, citrate,isethionate, or p-toluenesulfonate.

The anions X.sup.⊖ are those normally used to salify quaternary ammoniumions and are preferably chloride, bromide, iodide, acetate,hydrogensulfate, methanesulfonate, paratoluenesulfonate andbenzenesulfonate ions.

It is preferable to use the pharmaceutically acceptable anions, forexample chloride, methanesulfonate or benzenesulfonate.

In the present description, the alkyl groups or alkoxy groups are linearor branched; halogen atom is understood as meaning a chlorine, bromine,fluorine or iodine atom.

In the substituents of the group Z=phenyl, (C₁ -C₁₀)-alkyl is understoodas meaning for example a methyl, an ethyl, an n-propyl, an isopropyl, ann-butyl, an isobutyl, a sec-butyl, a tert-butyl, a pentyl or n-pentyl, ahexyl or n-hexyl, a heptyl or n-heptyl, an octyl or n-octyl, a nonyl orn-nonyl or a decyl or n-decyl; (C₃ -C₈)-cycloalkyl optionallysubstituted by a methyl is understood as meaning for example acyclopropyl, a cyclobutyl, a cyclopentyl, a 1-, 2- or3-methylcyclopentyl, a cyclohexyl, a 1-, 2-, 3- or 4-methylcyclohexyl, acycloheptyl or a cyclooctyl; (C₁ -C₁₀)-alkoxy is understood as meaningfor example a methoxy, an ethoxy, an n-propoxy, an isopropoxy, ann-butoxy, an isobutoxy, a sec-butoxy, a tert-butoxy, a pentoxy, ahexyloxy, a heptyloxy, a nonyloxy or a decyloxy; (C₃ -C₈)-cycloalkoxyoptionally substituted by a methyl is understood as meaning for examplea cyclopropoxy, a cyclohexyloxy, a 1-, 2-, 3- or 4-methylcyclohexyloxy,a cycloheptyloxy or a cyclooctyloxy; (C₁ -C₁₀)-alkylthio is understoodas meaning for example a methylthio, an ethylthio, an n-propylthio, anisopropylthio, an n-butylthio, an isobutylthio, a sec-butylthio, atert-butylthio, a pentylthio, a hexylthio, a heptylthio, an octylthio, anonylthio or a decylthio; (C₁ -C₆)-alkylcarbonyloxy is understood asmeaning for example an acetoxy, a propionyloxy, a butyryloxy, avaleryloxy, a caproyloxy or a heptanoyloxy; (C₁ -C₆)-alkylcarbonylaminois understood as meaning for example an acetylamino, a propionylamino, abutyrylamino, an isobutyrylamino, a valerylamino, a caproylamino or aheptanoylamino; (C₁ -C₄)-alkoxycarbonyl is understood as meaning forexample a methoxycarbonyl, an ethoxycarbonyl, an n-propoxycarbonyl, anisopropoxycarbonyl, an n-butoxycarbonyl, an isobutoxycarbonyl, asec-butoxycarbonyl or a tert-butoxycarbonyl; and (C₃-C₇)-cycloalkoxycarbonyl is understood as meaning for example acyclopropoxycarbonyl, a cyclobutoxycarbonyl, a cyclopentoxycarbonyl, acyclohexyloxycarbonyl or a cycloheptyloxycarbonyl.

Advantageously, the radical Z is a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen atom, more particularlya chlorine, fluorine or iodine atom, a trifluoromethyl, a (C₁-C₄)-alkyl, a hydroxyl or a (C₁ -C₄)-alkoxy; a naphthyl which isunsubstituted or monosubstituted or polysubstituted by a halogen, atrifluoromethyl, a (C₁ -C₄)-alkyl, a hydroxyl or a (C₁ -C₄)-alkoxy; apyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; or animidazolyl.

According to the present invention, the preferred compounds are those offormula (I) in which:

A is a divalent radical selected from:

A₁) --O--CO--

A₂) --CH₂ --O--CO--

A₃) --O--CH₂ --CO--

A₄) --O--CH₂ --CH₂ --

A₅) --N(R₁)--CO--

A₆) --N(R₁)--CO--CO--

A₇) --N(R₁)--CH₂ --CH₂ --

which:

R₁ is a hydrogen or a (C₁ -C₄ )-alkyl; and

Am is:

i--either a group Am₁ of the formula ##STR14## in which J₁ is: i₁--either a group ##STR15## which: Ar₂ is a pyridyl; or a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a hydroxyl, a (C₁ -C₄)-alkoxy, a (C₁-C₄)-alkyl and a trifluoromethyl, said substituents being identical ordifferent; and

R₂ is a hydrogen; a (C₁ -C₇)-alkyl; a benzyl; a formyl; or a (C₁-C₇)-alkylcarbonyl;

i₂ --or a group ##STR16## in which: Ar₂ defined above;

n is 0 or 1;

R₃ is a hydrogen; a (C₁ -C₇)-alkyl; a formyl; a (C₁ -C₇)-alkylcarbonyl;a cyano; a group --(CH₂)_(q) --OH; a group (C₁ -C₇)-alkyl--O--(CH₂)_(q)--; a group HCOO--(CH₂)_(q) --; a group (C₁ -C₇)-alkyl--COO--(CH₂)_(q)--; a group (C₁ -C₇)-alkyl--NHCOO--(CH₂)_(q) --; a group --NR₄ R₅ ; agroup --(CH₂)_(q) --NR₆ COR₇ ; a group --(CH₂)_(q) --NR₆ COOR₈ ; a group--(CH₂)_(q) --NR₆ SO₂ R₉ ; a group --(CH₂)_(q) --NR₆ CONR₁₀ R₁₁ ; agroup --CH₂ --NR₁₂ R₁₃ ; a group --CH₂ --CH₂ --NR₁₂ R₁₃ ; a carboxyl; a(C₁ -C₇)-alkoxycarbonyl; a group --CONR₁₀ R₁₁ ; a carboxymethyl; a (C₁-C₇)-alkoxycarbonylmethyl; a group --CH₂ --CONR₁₀ R₁₁ ; or a2-aminothiazol-4-yl in which the amino is free or substituted by one ortwo (C₁ -C₇)-alkyls;

or R₃ constitutes a double bond between the carbon atom to which it isbonded and the adjacent carbon atom of the piperidine ring;

q is 0, 1 or 2;

R₄ and R₅ are each independently a hydrogen or a (C₁ -C₇)-alkyl; R₅ canalso be a (C₃ -C₇)-cycloalkylmethyl, a benzyl or a phenyl; or R₄ and R₅,together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine and perhydroazepine;

R₆ is a hydrogen or a (C₁ -C₄)-alkyl;

R₇ is a hydrogen; a (C₁ -C₇)-alkyl; a vinyl; a phenyl; a benzyl; apyridyl; or a (C₃ -C₇)-cycloalkyl which is unsubstituted or substitutedby one or more methyls;

or R₆ and R₇ together are a group --(CH₂)_(p) --;

p is 3 or 4;

R₈ is a (C₁ -C₇)-alkyl or a phenyl;

R₉ is a (C₁ -C₇)-alkyl; an amino which is free or substituted by one ortwo (C₁ -C₇)-alkyls; or a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a (C₁ -C₇)-alkyl, a trifluoromethyl, a hydroxyl, a (C₁-C₇)-alkoxy, a carboxyl, a (C₁ -C₇)-alkoxycarbonyl, a (C₁-C₇)-alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁ -C₇)-alkyls, said substituents beingidentical or different;

R₁₀ and R₁₁ are each independently a hydrogen or a (C₁ -C₇)-alkyl; R₁₁can also be a (C₃ -C₇)-cycloalkyl, a (C₃ -C₇)-cycloalkylmethyl, ahydroxyl, a (C₁ -C₄)-alkoxy, a benzyl or a phenyl; or R₁₀ and R₁₁,together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine and perhydroazepine; and

R₁₂ and R₁₃ are each independently a hydrogen or a (C₁ -C₇)-alkyl; R₁₃can also be a (C₃ -C₇)-cycloalkylmethyl or a benzyl;

i₃ --or a group ##STR17## in which: R₃ is as defined above;

R₁₄ is a (C₁ -C₇)-alkyl or a (C₃ -C₇)-cycloalkyl; R₁₄ can also be eithera group --CONR₁₅ R₁₆ if R₃ is hydrogen, or a group --NR₁₅ R₁₆ if R₃ is acyano, a carboxyl, a (C₁ -C₇)-alkoxycarbonyl or a group --CONR₁₀ R₁₁ ;and

R₁₅ and R₁₆ are each independently a (C₁ -C₇)-alkyl; or R₁₅ and R₁₆,together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine and perhydroazepine;

ii--or a group Am₂ of the formula ##STR18## in which J₂ is: ii₁ --eithera group ##STR19## in which: Ar₃ is a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a hydroxyl, a (C₁ -C₄)-alkoxy, a (C₁ -C₄)-alkyl and atrifluoromethyl, said substituents being identical or different; and

R₂ is as defined above for J₁ ;

ii₂ --or a group ##STR20## in which: Ar₃ is as defined above;

n is 0 or 1;

Q is a (C₁ -C₆)-alkyl or a benzyl, said substituent being either inbeing either in the axial position or in the equatorial position; and

X.sup.⊖ is an anion;

iii--or a group Am₃ of the formula ##STR21## in which: Ar₂ is as definedabove;

n is 0 or 1; and

X.sup.⊖ is an anion;

iv--or a group Am₄ of the formula ##STR22## in which: Ar₂ is as definedabove;

n is 0 or 1;

X.sup.⊖ is an anion;

m is 2 or 3;

Ar₁ is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁ -C₄)-alkoxy, a (C₁ -C₄)-alkyl and a trifluoromethyl,said substituents being identical or different; a thienyl; abenzothienyl; a naphthyl; or an indolyl which is unsubstituted orN-substituted by a (C₁ -C₄)-alkyl or a benzyl;

T is a group selected from --CH₂ --Z, --CH(C₆ H₅)₂ and --C(C₆ H₅)₃ ; Tcan also be the group --CO--B--Z if A is a divalent radical selectedfrom --O--CH₂ --CH₂ -- and --N(R₁)--CH₂ --CH₂ --;

B is a direct bond or a methylene; and

Z is:

a phenyl which is unsubstituted or monosubstituted or polysubstituted bya substituent selected from a halogen atom; a trifluoromethyl; a cyano;a hydroxyl; a nitro; a phenyl which is unsubstituted or monosubstitutedor polysubstituted by a halogen, a trifluoromethyl, a (C₁ -C₄)-alkyl, ahydroxyl or a (C₁ -C₄)-alkoxy, said substituents being identical ordifferent; an amino which is unsubstituted or monosubstituted ordisubstituted by a (C₁ -C₄)-alkyl; a benzylamino; a carboxyl; a (C₁-C₁₀)-alkyl; a (C₃ -C₇)-cycloalkyl which is unsubstituted ormonosubstituted or polysubstituted by a methyl; a (C₁ -C₁₀)-alkoxy; a(C₃ -C₇)-cycloalkoxy which is unsubstituted or monosubstituted orpolysubstituted by a methyl; a mercapto; a (C₁ -C₁₀)-alkylthio; a (C₁-C₆)-alkylcarbonyloxy; a (C₁ -C₆)-alkylcarbonylamino; a benzoylamino; a(C₁ -C₄)-alkoxycarbonyl; a (C₃ -C₇)-cycloalkylcarbonyl; a carbamoylwhich is unsubstituted or monosubstituted or disubstituted by a (C₁-C₄)-alkyl; a ureido which is unsubstituted or monosubstituted ordisubstituted in the 3-position by a (C₁ -C₄)-alkyl or a (C₃-C₇)-cycloalkyl; and a (pyrrolidin-1-yl)carbonylamino, said substituentsbeing identical or different;

a naphthyl which is unsubstituted or monosubstituted or polysubstitutedby a halogen, a trifluoromethyl, a (C₁ -C₄)-alkyl, a hydroxyl or a (C₁-C₄)-alkoxy; or

a pyridyl, a thienyl, an indolyl, a quinolyl, a benzothienyl or animidazolyl;

and the salts thereof, where appropriate, with mineral or organic acids.

The compounds also preferred are those of formula (I) in which :

A is a divalent radical selected from:

A₁) --O--CO--

A₂) --CH₂ --O--CO--

A₃) --O--CH₂ --CO--

A₄) --O--CH₂ --CH₂ --

A₅) --N(R₁)--CO--

A₆) --N(R₁)--CO--CO--

A₇) --N(R₁)--CH₂ --CH₂ --

in which R₁ is a hydrogen or a (C₁ -C₄)-alkyl;

m is 2 or 3;

Ar₁ is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁ -C₄)-alkoxy, a (C₁ -C₄)-alkyl, a trifluoromethyl and amethylenedioxy, said substituents being identical or different; athienyl which is unsubstituted or substituted by a halogen atom; abenzothienyl which is unsubstituted or substituted by a halogen atom; anaphthyl which is unsubstituted or substituted by a halogen atom; anindolyl which is unsubstituted or N-substituted by a (C₁ -C₄)-alkyl or abenzyl; an imidazolyl which is unsubstituted or substituted by a halogenatom; a pyridyl which is unsubstituted or substituted by a halogen atom;or a biphenyl;

T is a group selected from CH₂ --Z, --CH(C₆ H₅)₂ and --C(C₆ H₅)₃ ; T canalso be the group --CO--B--Z if A is a divalent radical selected from--O--CH₂ --CH₂ -- and --N(R₁)--CH₂ --CH₂ --;

B is a direct bond or a methylene;

Z is an optionally substituted mono-, di- or tricyclic aromatic orheteroaromatic group; and

Am is:

i--either a group Am₁ of the formula ##STR23## which J₁ is: i₁ --eithera group ##STR24## in which: Ar₂ is a pyridyl; a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a hydroxyl, a (C₁ -C₄)-alkoxy, a (C₁-C₄)-alkyl, a trifluoromethyl, a nitro and a methylenedioxy, saidsubstituents being identical or different; a thienyl; a pyrimidyl; or animidazolyl which is unsubstituted or substituted by a (C₁ -C₄)-alkyl;and

R₂ is a hydrogen; a (C₁ -C₇)-alkyl; a benzyl; a formyl; or a (C₁-C₇)-alkylcarbonyl;

i₂ --or a group ##STR25## in which: Ar₂ is as defined above;

n is 0 or 1; and

R₃ is a group selected from:

(1) hydrogen;

(2) (C₁ -C₇)-alkyl;

(3) formyl;

(4) (C₁ -C₇)-alkylcarbonyl;

(5) cyano;

(6) --(CH₂)_(q) --OH;

(7) --(CH₂)_(q) --O--(C₁ -C₇)-alkyl;

(8) --(CH₂)_(q) --OCHO;

(9) --(CH₂)_(q) --OCOR₁₇ ;

(10) --(CH₂)_(q) --OCONH--(C₁ -C₇)-alkyl;

(11) --NR₄ R₅ ;

(12) --(CH₂)_(q) --NR₆ C(═W₁)R₇ ;

(13) --(CH₂)_(q) --NR₆ COOR₈ ;

(14) --(CH₂)_(q) NR₆ SO₂ R₉ ;

(15) --(CH₂)_(q) --NR₆ C(═W₁)NR₁₀ R₁₁ ;

(16) --CH₂ --NR₁₂ R₁₃ ;

(17) --CH₂ --CH₂ --NR₁₂ R₁₃ ;

(18) --COOH;

(19) (C₁ -C₇)-alkoxycarbonyl;

(20) --C(═W₁)NR₁₀ R₁₁ ;

(21) --CH₂ --COOH;

(22) (C₁ -C₇)-alkoxycarbonylmethyl;

(23) --CH₂ --C(═W₁)NR₁₀ R₁₁ ;

(24) --O--CH₂ CH₂ --OR₁₈ ;

(25) --NR₆ COCOR₁₉ ;

(26) --CO--NR₂₀ --NR₂₁ --R₂₂ ;

(27) ##STR26## (28) ##STR27## or R₃ constitutes a double bond betweenthe carbon atom to which it is bonded and the adjacent carbon atom ofthe piperidine ring;

q is 0, 1 or 2;

W₁ is an oxygen atom or a sulfur atom;

R₄ and R₅ are each independently a hydrogen or a (C₁ -C₇)-alkyl; R₅ canalso be a (C₃ -C₇)-cycloalkylmethyl, a benzyl or a phenyl; or R₄ and R₅,together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine, perhydroazepine and piperazine which isunsubstituted or substituted in the ₄ -position by a (C₁ -C₄)-alkyl;

R₆ is a hydrogen or a (C₁ -C₄)-alkyl;

R₇ is a hydrogen; a (C₁ -C₇)-alkyl; a vinyl; a phenyl; a benzyl; apyridyl; a (C₃ -C₇)-cycloalkyl which is unsubstituted or substituted byone or more methyls; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;

or R₆ and R₇ together are a group --(CH₂)_(p) --;

p is 3 or 4;

R₈ is a (C₁ -C₇)-alkyl or a phenyl;

R₉ is a (C₁ -C₇)-alkyl; an amino which is free or substituted by one ortwo (C₁ -C₇)-alkyls; or a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a (C₁ -C₇)-alkyl, a trifluoromethyl, a hydroxyl, a (C₁-C₇)-alkoxy, a carboxyl, a (C₁ -C₇)-alkoxycarbonyl, a (C₁-C₇)-alkylcarbonyloxy, a cyano, a nitro and an amino which is free orsubstituted by one or two (C₁ -C₇)-alkyls, said substituents beingidentical or different;

R₁₀ and R₁₁ are each independently a hydrogen or a (C₁ -C₇)-alkyl; R₁₁can also be a (C₃ -C₇)-cycloalkyl, a (C₃ -C₇)-cycloalkylmethyl, ahydroxyl, a (C₁ -C₄)-alkoxy, a benzyl or a phenyl; or R₁₀ and R₁₁,together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine and perhydroazepine;

R₁₂ and R₁₃ are each independently a hydrogen or a (C₁ -C₇)-alkyl; R₁₃can also be a (C₃ -C₇)-cycloalkylmethyl or a benzyl;

R₁₇ is a (C₁ -C₇)-alkyl; a (C₃ -C₇)-cycloalkyl which is unsubstituted orsubstituted by one or more methyls; a phenyl; or a pyridyl;

R₁₈ is a hydrogen; a (C₁ -C₇)-alkyl; a formyl; or a (C₁ -C₇)-alkylcarbonyl;

R₁₉ is a (C₁ -C₄)-alkoxy;

R₂₀ is a hydrogen or a (C₁ -C₇)-alkyl;

R₂₁ and R₂₂ are each independently a hydrogen or a (C₁ -C₇)-alkyl;

or alternatively R₂₁ and R₂₂, together with the nitrogen atom to whichthey are bonded, form a heterocycle selected from pyrrolidine,piperidine and morpholine;

R₂₃ is a hydrogen or a (C₁ -C₇)-alkyl; and

R₂₄ and R₂₅ are each independently a hydrogen or a (C₁ -C₇)-alkyl; R₂₅can also be a formyl or a (C₁ -C₇)-alkylcarbonyl;

i₃ --or a group ##STR28## in which: R₃ is as defined above;

R₁₄ is a (C₁ -C₇)-alkyl or a (C₃ -C₇)-cycloalkyl; R₁₄ can also be eithera group --CONR₁₅ R₁₆ if R₃ is hydrogen, or a group --NR₁₅ R₁₆ if R₃ is acyano, a carboxyl, a (C₁ -C₇)-alkoxycarbonyl or a group --C(═W₁)NR₁₀ R₁₁; and

R₁₅ and R₁₆ are each independently a (C₁ -C₇)-alkyl; or R₁₅ and R₁₆,together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine,morpholine, thiomorpholine and perhydroazepine;

ii--or a group Am₂ of the formula ##STR29## in which J₂ is: ii₁ --eithera group ##STR30## in which: Ar₃ is a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a substituent selected from ahalogen atom, a hydroxyl, a (C₁ -C₄)-alkoxy, a (C₁ -C₄)-alkyl and atrifluoromethyl, said substituents being identical or different; and

R₂ is as defined above for J₁ ;

ii₂ --or a group ##STR31## in which: Ar₃ is as defined above;

n is 0 or 1;

Q is a (C₁ -C₆)-alkyl or a benzyl, said substituent being either in theaxial position or in the equatorial position; and

X.sup.⊖ is an anion;

iii--or a group Am₃ of the formula ##STR32## which: Ar₂ is as definedabove;

n is 0 or 1; and

X.sup.⊖ is an anion;

iv--or a group Am₄ of the formula ##STR33## in which: Ar₂ is as definedabove;

n is 0 or 1; and

X.sup.⊖ is an anion;

and the salts thereof, where appropriate, with mineral or organic acids.

Another group of preferred compounds according to the present inventionconsists of those of the formula ##STR34## in which: Aa is a divalentradical selected from --O--CO--; --CH₂ --O--CO--; --O--CH₂ --CO--;--N(R₁)--CO-- and --N(R₁)--CO--CO--, in which R₁ is a hydrogen or a (C₁-C₄)-alkyl;

Am_(a) is:

either a group Am_(2a) of the formula ##STR35## n is 0 or 1; Q is asdefined above for a compound of formula (I) and is in the axialposition;

X.sup.⊖ is a pharmaceutically acceptable anion;

Ar₂ and Ar₃ are as defined above for a compound of formula (I);

Ar_(1a) is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁ -C₄)-alkoxy, a (C₁ -C₄)-alkyl and a trifluoromethyl,said substituents being identical or different; and

Za is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, atrifluoromethyl, a (C₁ -C₁₀)-alkyl, a (C₁ -C₁₀)-alkoxy and a hydroxyl,said substituents being identical or different.

Among these compounds, those of the formula ##STR36## in which: Aa andAm_(a) are as defined above for a compound of formula (Ia);

Ar'_(1a) is a 3,4-dichlorophenyl or a 3,4-difluorophenyl; and

Z'a is a 3,5-bis(trifluoromethyl)phenyl, a 3,5-dimethylphenyl or a2,4-bis(trifluoromethyl)phenyl,

are particularly preferred.

Another group of preferred compounds according to the invention consistsof those of the formula ##STR37## in which: Ab is the divalent radical--O--CH₂ --CH₂ --, --N(R₁)--CH₂ --CH₂ -- or --O--CH₂ --,

in which R₁ is a hydrogen or a (C₁ -C₄)-alkyl;

Am_(b) is: ##STR38## n is 0 or 1; Q is as defined above for a compoundof formula (I) and is in the axial position;

X.sup.⊖ is a pharmaceutically acceptable anion;

Ar₂, Ar₃ and R₃ are as defined above for a compound of formula (I); and

Ar_(1a) and Za are as defined above;

and the salts thereof with mineral or organic acids.

Among these compounds, those of the formula ##STR39## in which: Am_(b)is as defined above for a compound of formula (Ib);

A'b is the divalent radical --O--CH₂ --CH₂ -- or --N(R₁)--CH₂ --CH₂ --;

Ar'_(1a) is as defined above for a compound of formula (I'a); and

Z"a is a phenyl substituted in the 3-position by a halogen or a (C₁-C₁₀)-alkoxy group,

and the salts thereof with mineral or organic acids, are particularlypreferred.

Another group of preferred compounds according to the invention consistsof those of the formula ##STR40## in which: Ac is a divalent radicalselected from --O--CH₂ --CO--; --CH₂ --O--CO-- and --O--CO--;

Am_(c) is a group Am_(1a) of the formula ##STR41## n is 0 or 1; Ar₂ andR₃ are as defined above for a compound of formula (I); and

Ar_(1a) and Za are as defined above;

and the salts thereof with mineral or organic acids.

Among these compounds, those of the formula ##STR42## in which: Ac,Am_(c) and Ar'_(1a) are as defined above,

and the salts thereof with mineral or organic acids, are particularlypreferred.

Another group of preferred compounds according to the invention consistsof those of the formula ##STR43## in which: Ab, Am_(c), Ar_(1a) and Zaare as defined above;

and the salts thereof with mineral or organic acids.

Among these compounds, those of the formula ##STR44## in which: A'b,Am_(c) and Ar'_(1a) are as defined above,

and the salts thereof with mineral or organic acids, are particularlypreferred.

Among the compounds of formulae (Ia) and (I'a) above, those in which:

Ar₂ is a pyridyl; or a phenyl which is unsubstituted or monosubstitutedor polysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁ -C₄)-alkoxy, a (C₁ -C₄)-alkyl and a trifluoromethyl,said substituents being identical or different; and the salts thereofwith mineral or organic acids

are particularly preferred

Among the compounds of formulae (I'b), (Ic), (I'c) and (I'd) above,those in which:

Ar₂ is a pyridyl; or a phenyl which is unsubstituted or monosubstitutedor polysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁ -C₄)-alkoxy, a (C₁ -C₄)-alkyl and a trifluoromethyl,said substituents being identical or different, and

R₃ is a hydrogen; a (C₁ -C₇)-alkyl; a formyl; a (C₁ -C₇)-alkylcarbonyl;a cyano; a group --(CH₂)_(q) --OH; a group (C₁ -C₇) -alkyl--O--(CH₂)_(q)--; a group HCOO--(CH₂)_(q) --; a group (C₁ -C₇)-alkyl--COO--(CH₂)_(q)--; a group (C₁ -C₇)--alkyl--NHCOO--(CH₂)_(q) --; a group --NR₄ R₅ ; agroup --(CH₂)_(q) --NR₆ COR₇ ; a group --(CH₂ )_(q) --NR₆ COOR₈ ; agroup --(CH₂)_(q) --NR₆ SO₂ R₉ ; a group --(CH₂)_(q) --NR₆ CONR₁₀ R₁₁ ;a group --CH₂ --NR₁₂ R₁₃ ; a group --CH₂ --CH₂ --NR₁₂ R₁₃ ; a carboxyl;a (C₁ -C₇)-alkoxycarbonyl; a group --CONR₁₀ R₁₁ ; a carboxymethyl; a (C₁-C₇)-alkoxycarbonylmethyl; a group --CH₂ --CONR₁₀ R₁₁ ; or a2-aminothiazol-4-yl in which the amino is free or substituted by one ortwo (C₁ -C₇)-alkyls;

or R₃ constitutes a double bond between the carbon atom to which it isbonded and the adjacent carbon atom of the piperidine ring;

q is 0, 1 or 2;

and the salts thereof, with mineral or organic acids, are particularlypreferred.

Among the compounds of formulae (Ib) and (Id), those in which:

Ab is the divalent radical --O--CH₂ --CH₂ -- or --N(R₁)--CH₂ --CH₂ --,

Ar₂ is a pyridyl; or a phenyl which is unsubstituted or monosubstitutedor polysubstituted by a substituent selected from a halogen atom, ahydroxyl, a (C₁ -C₄)-alkoxy, a (C₁ -C₄)-alkyl and a trifluoromethyl,said substituents being identical or different, and

R₃ is a hydrogen: a (C₁ -C₇)-alkyl; a formyl; a (C₁ -C₇)-alkylcarbonyl;a cyano; a group --(CH₂)_(q) --OH; a group (C₁ -C₇)-alkyl--O--(CH₂)_(q)--; a group HCOO--(CH₂)_(q) --; a group (C₁ -C₇)-alkyl--COO--(CH₂)_(q)--; a group (C₁ -C₇)-alkyl--NHCOO--(CH₂)_(q) --; a group --NR₄ R₅ ; agroup --(CH₂)_(q) --NR₆ COR₇ ; a group --(CH₂)_(q) --NR₆ COOR₈ ; a group--(CH₂)_(q) --NR₆ SO₂ R₉ ; a group --(CH₂)_(q) --NR₆ CONR₁₀ R₁₁ ; agroup --CH₂ --NR₁₂ R₁₃ ; a group --CH₂ --CH₂ --NR₁₂ R₁₃ ; a carboxyl; a(C₁ -C₇)-alkoxycarbonyl; a group --CONR₁₀ R₁₁ ; a carboxymethyl; a (C₁-C₇)-alkoxycarbonylmethyl; a group --CH₂ --CONR₁₀ R₁₁ ; or a2-aminothiazol-4-yl in which the amino is free or substituted by one ortwo (C₁ -C₇)-alkyls;

or R₃ constitutes a double bond between the carbon atom to which it isbonded and the adjacent carbon atom of the piperidine ring;

q is 0, 1 or 2

and the salts thereof, with mineral organic acids, are particularlypreferred.

Another group of preferred compounds according to the invention consistsof those of the formula ##STR45## in which Ab, Am_(c), Ar_(1a) and Zaare as defined above;

and the salts thereof with mineral or organic acids.

Another group of preferred compounds according to the invention consistsof those of the formula: ##STR46## in which Aa, Am_(c), Ar_(1a) and Zaare as defined above;

and the salts thereof with mineral or organic acids.

4-Benpoyl-2-(3,4-difluorophenyl)-2-[2-[4-(N',N'-dimethylureido)-4-phenylpiperid-1-yl]ethyl]morpholine,in optically pure form, preferably in the form of the (+) isomer, andthe salts thereof with mineral or organic acids, are very particularlypreferred.

5-(3,4-Difluorophenyl)-5-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-onewith a pharmaceutically acceptable anion, in optically pure form,preferably in the form of the (+) isomer, is very particularlypreferred.

According to another of its features, the present invention relates to amethod of preparing the compounds of formula (I) and the salts thereof,which comprises:

1) treating a compound of the formula ##STR47## in which m, Ar₁ and Aare as defined above for a compound of formula (I) and E is hydrogen oran O-protecting group,

either with a functional derivative of an acid of the formula

    HOCO--B--Z                                                 (III)

in which B and Z are as defined above for (I), if it is intended toprepare a compound of formula (I) in which T is --CO--B--Z,

or with a halogenated derivative of the formula

    Hal--CH.sub.2 --Z                                          (IV)

in which Z is as defined above and Hal is a halogen, preferably bromineor chlorine, if it is intended to prepare a compound of formula (I) inwhich T is --CH₂ --Z,

or with a halogenated derivative of the formula

    Hal--CH(C.sub.6 H.sub.5).sub.2                             (V)

if it is intended to prepare a compound of formula (I) in which T is agroup --CH(C₆ H₅)₂,

or with a halogenated derivative of the formula

    Hal--C--(C.sub.6 H.sub.5).sub.3                            (VI)

if it is intended to prepare a compound of formula (I) in which T is agroup --C(C₆ H₅)₃,

to give a compound of the formula ##STR48## 2) optionally removing theO-protecting group by reaction with an acid or a base to give thealcohol of the formula ##STR49## 3) treating the alcohol (VIII) with acompound of the formula

    Y--SO.sub.2 --Cl                                           (IX)

in which Y is a methyl, phenyl, tolyl or trifluoromethyl group, to givea compound of the formula ##STR50## 4) reacting the compound (X): eitherwith a cyclic secondary amine of the formula ##STR51## in which J'₁ is:either a group ##STR52## in which Ar₂ is as defined for (I) and R'₂ iseither R₂ as defined for (I) or a precursor of R₂ ;

or a group ##STR53## in which Ar₂ and n are as defined for (I) and R'₃is either R₃ as defined for (I) or a precursor of R₃, it beingunderstood that if R'₃ is a hydroxyl or an amino, these groups can beprotected;

or a group ##STR54## in which R₁₄ is as defined for (I) and R'₃ is asdefined above; or with a tertiary amine of the formula ##STR55## inwhich J₂ and Q are as defined for (I); or with a cyclic tertiary amineof the formula ##STR56## in which Ar₂ and n are as defined for (I); orwith a compound of the formula ##STR57## in which Ar₂ and n are asdefined for (I); and 5)--either, in the case where a cyclic secondaryamine of formula (XI) is used, and after deprotection of the hydroxylgroup or the amino group represented by R'₃, if appropriate, or optionalconversion of R'₂ to R₂ or R'₃ to R₃, optionally converting theresulting product to a salt thereof;

or, in the case where a tertiary amine of formula (XII), a cyclictertiary amine of formula (XIII) or a compound of formula (XIV) is used,isolating the resulting product in the form of a sulfonate and, ifappropriate, a sulfonic acid salt, or optionally exchanging theresulting anion and, if appropriate, acid salt with anotherpharmaceutically acceptable anion and, if appropriate, another salt witha pharmaceutically acceptable mineral or organic acid.

In one variant of the method, if Am is a group Am₁,

1') a compound of formula (VIII) as defined above is oxidized to give acompound of the formula ##STR58## in which m, Ar₁, A and T are asdefined for a compound of formula (I);

2') the compound of formula (XXXVIII) is reacted with a compound offormula (XI) as defined above, in the presence of an acid, and theiminium salt formed as an intermediate is then reduced by means of areducing agent; and

3') after deprotection of the hydroxyl groups or amino groups, ifappropriate, or optional conversion of R'₂ to R₂ or R'₃ to R₃, theresulting product is optionally converted to a salt thereof.

The compounds of the formula ##STR59## in enantiomerically pure form orin racemic form are novel and form part of the invention.

The compounds of the formula ##STR60## in enantiomerically pure form orin racemic form are novel and form part of the invention.

The compounds of formulae (II) and (VII) in which E is hydrogen areparticularly preferred.

The compounds of the formula ##STR61## in enantiomerically pure form orin racemic form are novel and form part of the invention.

The compounds of the formula ##STR62## in enantiomerically pure form orin racemic form are novel and form part of the invention.

In formulae (II), (VII), (X) and (XXXVIII), m and the groups E, A, Ar₁,T and Y are as defined above.

Thus, according to another of its features, the present inventionrelates to compounds of the formula ##STR63## in which: m, Ar₁ and A areas defined for a compound of formula (I);

R_(I) is two hydrogen atoms and R_(II) is:

either a group --O--E, in which E is a hydrogen atom or an O-protectinggroup,

or a group --O--SO₂ --Y, in which Y is a methyl, phenyl, tolyl ortrifluoromethyl group;

or alternatively R_(I) is an oxygen atom and R_(II) is a hydrogen atom;and

T' is T as defined for a compound of formula (I); T' can also behydrogen if R_(I) is 2 hydrogen atoms and R_(II) is simultaneously agroup --O--E--,

in enantiomerically pure form or in racemic form.

Thus, if E is an O-protecting group, this is selected from theconventional O-protecting groups well known to those skilled in the art,such as, for example, tetrahydropyran-2-yl, benzoyl or a (C₁-C₄)-alkylcarbonyl.

The O-protecting groups which may be used to obtain a compound offormula (I) in which R₃ is a hydroxyl are the conventional O-protectinggroups well known to those skilled in the art, as defined above for E.

The N-protecting groups which may be used to obtain a compound offormula (I) in which R₃ is an amino are the conventional N-protectinggroups well known to those skilled in the art, such as, for example, thetrityl, methoxytrityl, tert-butoxycarbonyl or benzyloxycarbonyl group.

In particular, if the O-protecting group used is an acetyl group, thecompound of formula (I) obtained represents the final product in whichR₃ is an acetoxy, or if the N-protecting group used is atertbutoxycarbonyl group, the compound of formula (I) obtainedrepresents the final product in which R₃ is a tert-butoxycarbonylamino.

In step 1), the functional derivative of the acid (III) used is the aciditself or alternatively one of the functional derivatives which reactwith amines, for example an anhydride, a mixed anhydride, the acidchloride or an activated ester such as the paranitrophenyl ester.

If the acid of formula (III) itself is used, the reaction is carried outin the presence of a coupling agent used in peptide chemistry, such as1,3-dicyclohexylcarbodiimide orbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate,in the presence of a base such as triethylamine orN,N-diisopropylethylamine, in an inert solvent such as dichloromethaneor N,N-dimethylformamide, at a temperature between 0° C. and roomtemperature.

If an acid chloride is used, the reaction is carried out in an inertsolvent such as dichloromethane or benzene, in the presence of a basesuch as triethylamine or N-methylmorpholine, and at a temperaturebetween -60° C. and room temperature.

If a halogenated derivative of formula (IV), (V) or (VI) is used, thereaction is carried out in an inert solvent such as tetrahydrofuran,N,N-dimethylformamide or dimethyl sulfoxide, in the presence of a basesuch as potassium tert-butylate, sodium hydride or lithiumdiisopropylamide, and at a temperature between 0° C. and 80° C.

The resulting compound of formula (VII) is deprotected in step 2), ifappropriate, by the methods known to those skilled in the art. Forexample, if E is a tetrahydropyran-2-yl group, the deprotection iseffected by acid hydrolysis using hydrochloric acid in a solvent such asether or methanol or a mixture of these solvents, or using pyridiniump-toluenesulfonate in a solvent such as methanol, or else using anAmberlyst® resin in a solvent such as methanol. The reaction is carriedout at a temperature between room temperature and the reflux temperatureof the solvent. If E is a benzoyl group or a (C₁ -C₄)-alkylcarbonylgroup, the deprotection is effected by hydrolysis in an alkaline mediumusing for example an alkali metal hydroxide such as sodium hydroxide,potassium hydroxide or lithium hydroxide, in an inert solvent such aswater, methanol, ethanol or dioxane or a mixture of these solvents, at atemperature between 0° C. and the reflux temperature of the solvent.

In step 3), the reaction of the alcohol of formula (VIII) with asulfonyl chloride of formula (IX) is carried out in the presence of abase such as triethylamine, pyridine, N,N-diisopropylethylamine orN-methylmorpholine, in an inert solvent such as dichloromethane, benzeneor toluene, at a temperature between -20° C. and the reflux temperatureof the solvent.

The resulting compound of formula (X) is reacted in step 4) with acompound of formula (XI), (XII), (XIII) or (XIV) by differentprocedures.

If a compound of formula (X) is reacted with a compound of formula (XI),the reaction is carried out in an inert solvent such asN,N-dimethylformamide, acetonitrile, methylene chloride, toluene orisopropanol, and in the presence or absence of a base. If a base isused, this is selected from organic bases such as triethylamine,N,N-diisopropylethylamine and N-methylmorpholine, or from alkali metalcarbonates or bicarbonates such as potassium carbonate, sodium carbonateand sodium bicarbonate. In the absence of a base, the reaction iscarried out using an excess of the compound of formula (XI) and in thepresence of an alkali metal iodide such as potassium iodide or sodiumiodide. If --A-- in the compound of formula (X) is the divalent radical--O--CO-- or --CH₂ --O--CO--, the reaction is carried out at atemperature between room temperature and 80° C. If --A-- in the compoundof formula (X) is the divalent radical --O--CH₂ --CO--, --O--CH₂ --CH₂--, --N(R₁)--CO--CO--, --N(R₁)--CH₂ --CH₂ --, --N(R₁)--CO-- or --O--CH₂--, the reaction is carried out at a temperature between roomtemperature and 100° C.

If a compound of formula (X) is reacted with a compound of formula (XII)or (XIII), the reaction is carried out in a polar aprotic solvent suchas acetonitrile, N,N-dimethylformamide or N,N-dimethylphenylacetamide,in an ether such as tetrahydrofuran, dioxane or methyl tert-butyl ether,or in a ketone such as methyl ethyl ketone. If --A-- in the compound offormula (X) is the divalent radical --O--CO-- or --CH₂ --O--CO--, thereaction is carried out at a temperature between room temperature and60° C. If --A-- in the compound of formula (X) is the divalent radical--O--CH₂ --CO--, --O--CH₂ --CH₂ --, --N(R₁)--CO--CO--, --N(R₁)--CH₂--CH₂ --, --N(R₁)--CO-- or --O--CH₂ --, the reaction is carried out at atemperature between room temperature and 100° C.

If a compound of formula (X) is reacted with a compound of formula(XIV), the reaction is carried out in a polar aprotic solvent such asacetonitrile, N,N-dimethylformamide or N,N-dimethylphenylacetamide, inan ether such as tetrahydrofuran, dioxane or methyl tertbutyl ether, orin a ketone such as methyl ethyl ketone. The reaction is carried out ata temperature between room temperature and 100° C.

In step 1') of the variant of the method, an alcohol of formula (VIII)is oxidized to an aldehyde of formula (XXXVIII). The oxidation reactionis carried out using for example oxalyl chloride, dimethyl sulfoxide andtriethylamine in a solvent such as dichloromethane and at a temperaturebetween -78° C. and room temperature.

Then, in step 2'), the compound of formula (XI) is reacted with analdehyde of formula (XXXVIII) in the presence of an acid such as aceticacid, in an alcoholic solvent such as methanol, to form in situ anintermediate imine, which is reduced chemically using for example sodiumcyanoborohydride, or catalytically using hydrogen and a catalyst such aspalladium-on charcoal or Raney® nickel.

The compounds of formula (I) according to the invention are finallyobtained after deprotection of the hydroxyl groups or amino groups, ifappropriate, or optional conversion of R'₂ to R₂ and R'₃ to R₃.

The resulting products of formula (I) are:

either isolated in the form of the free base or a salt, by theconventional techniques, if Am is Am₁,

or, if Am is Am₂, Am₃ or Am₄, isolated in the form of sulfonate anion(YSO₃.sup.⊖) or alternatively the sulfonate anion of the resultingquaternary salt is optionally exchanged with another pharmaceuticallyacceptable anion.

If the compound of formula (I) in which Am is Am₁ is obtained in theform of the free base, salification is effected by treatment with thechosen acid in an organic solvent. Treatment of the free base, dissolvedfor example in an ether such as diethyl ether, in an alcohol such aspropan-2-ol, in acetone or in dichloromethane, with a solution of thechosen acid in the same solvent gives the corresponding salt, which isisolated by the conventional techniques.

The hydrochloride, hydrobromide, sulfate, hydrogensulfate,dihydrogenphosphate, methanesulfonate, oxalate, maleate, fumarate,naphthalene-2-sulfonate and benzenesulfonate, for example, are preparedin this way.

When the reaction is complete, the compounds of formula (I) in which Amis Am₁ can be isolated in the form of a salt thereof, for example thehydrochloride or the oxalate; in this case, if necessary, the free basecan be prepared by the neutralization of said salt with a mineral ororganic base such as sodium hydroxide or triethylamine, or with analkali metal carbonate or bicarbonate such as sodium or potassiumcarbonate or bicarbonate.

The sulfonate anion YSO₃.sup.⊖ originating from the reaction between thecompound of formula (XII), (XIII) or (XIV) and the compound of formula(X) can be exchanged, in situ or after isolation of the compound offormula (I) in which Am is a group Am₂, Am₃ or Am₄ in which X.sup.⊖ isthe ion YSO₃.sup.⊖, with another anion X.sup.⊖ by the conventionalmethods, for example by exchange in solution with saturated sodiumchloride solution or with hydrochloric acid solution if X.sup.⊖ is achloride anion, or by exchange of the anion via elution of the compound(I) on an ion exchange resin, for example Amberlite IRA68® or DuoliteA375®.

When the reaction is complete, the compounds of formula (I) in which Amis Am₂ are obtained in the form of a mixture of the axial and equatorialisomers. The isomers are separated by the usual methods, for example bychromatography or recrystallization.

The compounds of formula (II) are prepared by different procedures.

The compounds of formula (II) in which --A-- is the divalent radical--CH₂ --O--CO-- and E is hydrogen or an O-protecting group are preparedaccording to SCHEME 1 below, in which m and Ar₁ are as defined for acompound of formula (I) and Pr is an O-protecting group as defined abovefor E. ##STR64##

In step a1 of SCHEME 1, a compound of formula (XV) is reacted with acompound of formula (XVI) by the method described in patent applicationsEP-A-0428434 and EP-A-0474561.

The resulting compound (XVII) is reacted in step b1 with aqueousformaldehyde solution in the presence of a base such as1,8-diazabicyclo[5.4.0]undec-7-ene, in a solvent such as1,2-dimethoxyethane and at a temperature between room temperature andthe reflux temperature of the solvent.

The nitrile derivative of formula (XVIII) is reduced in step c1 to givethe primary amine of formula (XIX). This reduction can be effected bymeans of hydrogen in the presence of a catalyst such as Raney nickel,platinum oxide or palladium-on-charcoal, in an inert solvent such as analcohol, for example ethanol, by itself or mixed with aqueous ammonia,or by means of a reducing agent such as lithium aluminum hydride,diisobutylaluminum hydride or borane in THF, in a solvent such astoluene, hexane, petroleum ether, xylene or tetrahydrofuran. Thereaction is carried out at a temperature between 0° C. and 70° C.

In step d1, the compound (XIX) is reacted with a reactive derivative ofcarbonic acid, such as phosgene, in solution in toluene, or1,1'-carbonyldiimidazole, in the presence of a base such astriethylamine, N,N-diisopropylethylamine or N-methylmorpholine, in achlorinated solvent such as dichloromethane or 1,2-dichloroethane, or anether such as tetrahydrofuran, and at a temperature between -70° C. androom temperature, to give a compound of the expected formula (II) inwhich E is an O-protecting group.

Using the methods described above, the O-protecting group is removed byhydrolysis (step e1) to give the compound of formula (II) in which E ishydrogen.

The compounds of formula (II) in which --A-- is the divalent radical--O--CH₂ --CO-- and E is hydrogen or an O-protecting group are preparedaccording to SCHEME 2 below, in which m and Ar₁ are as defined for acompound of formula (I). Pr₁ and Pr₂ are the O-protecting group Pr asdefined above for E; more particularly, Pr₁ is an O-protecting grouphydrolyzable in an acid medium and Pr₂ is an O-protecting grouphydrolyzable in a basic medium. ##STR65##

In step a2 of SCHEME 2, the synthesis of a cyanohydrin of formula (XXI)from an aldehyde of formula (XX) is effected by the methods well knownto those skilled in the art, such as, for example, the one described inOrganic Syntheses; Wiley, N.Y., 1932; Collect. vol. 1, p. 336, or by anadaptation of this method utilizing the action of sodium metabisulfiteand potassium cyanide in aqueous solution.

In step b2, the hydroxyl group of the compound of formula (XXI) isprotected by the methods known to those skilled in the art.

The resulting compound of formula (XXII) is treated in step c2 with astrong base such as lithium diisopropylamide, potassium tert-butylate orsodium hydride, to give a carbanion, which is reacted with a compound ofthe formula Hal-(CH₂)_(m) --O--Pr₂, in which Hal is a halogen,preferably bromine or chlorine, to give the compound of formula (XXIII).The reaction is carried out in an inert solvent such as an ether (forexample tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane), an amide(for example N,N-dimethylformamide) or an aromatic hydrocarbon (forexample toluene or xylene), at a temperature between -70° C. and +60° C.

The nitrile derivative of formula (XXIII) is reduced in step d2 by themethods described above to give the primary amine of formula (XXIV).

In step e2, the compound of formula (XXIV) is reacted with a compound ofthe formula Hal-CO--CH₂ -Hal, in which Hal is a halogen, preferablychlorine or bromine, in the presence of a base such as a tertiary amine(for example triethylamine, N-methylmorpholine or pyridine), to give acompound of formula (XXV). The reaction is carried out in an inertsolvent such as a chlorinated solvent (for example dichloromethane,dichloroethane or chloroform), an ether (for example tetrahydrofuran ordioxane) or an amide (for example N,N-dimethylformamide), at atemperature between -70° C. and room temperature.

In step f2, the O-protecting group Pr₁ is removed from the compound offormula (XXV) by acid hydrolysis using the methods described above.

Alternatively, the O-protecting group Pr₁ is removed from the compoundof formula (XXIV) by acid hydrolysis in step j2, after which theresulting compound (XXVII) is reacted in step k2 with a compound of theformula Hal-CO--CH₂ -Hal by the methods described above in step e2.

The resulting compound of formula (XXVI) is cyclized in the presence ofa base to give the compound of the expected formula (II). If it isdesired to obtain a compound of formula (II) in which E is a protectinggroup Pr₂, a base such as an alkali metal carbonate (for examplepotassium carbonate), an alkali metal hydride (for example sodiumhydride) or potassium tert-butylate is used in an inert solvent such asan aromatic hydrocarbon (for example xylene or toluene), an amide (forexample N,N-dimethylformamide) or an ether (for exampletetrahydrofuran), at a temperature between -30° C. and the refluxtemperature of the solvent (step g2). If it is desired to obtain acompound of formula (II) in which E is hydrogen, a base such as analkali metal hydroxide (for example sodium hydroxide or potassiumhydroxide) in concentrated aqueous solution is used in a solvent such asan alkanol (for example propan-2-ol) or an amide (for exampleN,N-dimethylformamide) or a mixture of these solvents, at a temperaturebetween room temperature and the reflux temperature of the solvent (steph2).

If appropriate, a compound of formula (II) in which E is an O-protectinggroup Pr₁ is prepared in step i2 by the methods known to those skilledin the art.

The compounds of formula (II) in which --A-- is the divalent radical--O--CH₂ --CH₂ -- and E is hydrogen or an O-protecting group areprepared according to SCHEME 3 below, in which m and Ar₁ are as definedfor a compound of formula (I) and Pr₁ and Pr₂ are as defined in SCHEME 2above. ##STR66##

In step a3 of SCHEME 3, a compound of formula (II) in which --A-- is thedivalent radical --O--CH₂ --CO-- and E is hydrogen or an O-protectinggroup, obtained according to SCHEME 2, is reduced. The reduction iseffected by means of a reducing agent such as lithium aluminum hydride,diisobutylaluminum hydride, sodium borohydride or borane in THF, in aninert solvent such as tetrahydrofuran, diethyl ether,1,2-dimethoxyethane or toluene, at a temperature between roomtemperature and the reflux temperature of the solvent.

The compounds of formula (I) in which --A-- is the divalent radical--O--CO-- and E is hydrogen or an O-protecting group are preparedaccording to SCHEME 4 below, in which m and Ar₁ are as defined for acompound of formula (I) and Pr₁ and Pr₂ are as defined in SCHEME 2above. ##STR67##

In step a4 of SCHEME 4, the O-protecting group Pr₁ of the compound offormula (XXIV), obtained in step d2 of SCHEME 2, is removed by acidhydrolysis using the methods described above.

The resulting compound of formula (XXVII) is reacted in step b4 with areactive derivative of carbonic acid, such as 1,1'-carbonyldiimidazole,phosgene in toluene, or p-nitrophenyl chloroformate, in the presence ofa base such as triethylamine, N,N-diisopropylethylamine orN-methylmorpholine, to give a compound of the expected formula (II) inwhich E is an O-protecting group. The reaction is carried out in aninert solvent such as a chlorinated solvent (for example1,2-dichloroethane or dichloromethane), an ether such astetrahydrofuran, an amide such as N,N-dimethylformamide or an aromaticsolvent such as toluene, at a temperature between -60° C. and roomtemperature.

Using the methods described above, the O-protecting group Pr₂ is removedby basic hydrolysis (step c4) to give the compound of formula (II) inwhich E is hydrogen.

The compounds of formula (II) in which --A-- is the divalent radical--N(R₁)--CO--CO-- and E is hydrogen or an O-protecting group areprepared according to SCHEME 5 below, in which m, Ar₁ and R₁ are asdefined for a compound of formula (I) and Pr₁ is as defined above.##STR68##

In step a5 of SCHEME 5, an α-amino nitrile compound of formula (XXVIII)is prepared from an aldehyde of formula (XX) by the method described inTetrahedron Letters, 1984, 25 (41), 4583-4586, using an amine of theformula H₂ N--R₁.

The amino group of the compound of formula (XXVIII) is protected in stepb5 by an N-protecting group such as tert-butoxycarbonyl (Boc) orbenzyloxycarbonyl, for example, using the methods known to those skilledin the art. The tert-butoxycarbonyl group is illustrated in SCHEME 5above.

The resulting compound of formula (XXIX) is treated in step c5 with astrong base to form a carbanion, which is reacted with a compound of theformula Hal-(CH₂)_(m) --O--Pr₁ to give a compound of formula (XXX). Thereaction is carried out by the method described in step c2 of SCHEME 2.

The nitrile derivative of formula (XXX) is reduced in step d5 by themethods described above to give the primary amine of formula (XXXI).

In step e5, the O-protecting group and the N-protecting group areremoved from the compound of formula (XXXI) by acid hydrolysis withhydrochloric acid or trifluoroacetic acid, for example, in a solventsuch as an alcohol (for example methanol), an ether (for example diethylether, dioxane or tetrahydrofuran) or a chlorinated solvent (for exampledichloromethane), at a temperature between 0° C. and the refluxtemperature of the reaction mixture.

In step f5the compound of the expected formula (II) is prepared byapplication or adaptation of the method described by R. Granger, H.Orzalesi and Y. Robbe in Trav. Soc. Pharm. Montpellier, 1965, 25, Fasc.4, 313-317, using the reaction of a compound of formula (XXXII) withdiethyl oxalate in an alcoholic solvent such as ethanol, or an aromaticsolvent such as toluene, or a mixture of these solvents, at atemperature between room temperature and the reflux temperature of thereaction mixture.

If appropriate, a compound of formula (II) in which E is an O-protectinggroup Pr₁ is prepared in step g5 by the methods known to those skilledin the art.

The compounds of formula (II) in which --A-- is the divalent radical--N(R₁)--CH₂ --CH₂ -- and E is hydrogen or an O-protecting group areprepared according to SCHEME 6 below, in which m, R₁ and Ar₁ are asdefined for a compound of formula (I) and Pr₁ is an O-protecting groupas defined above for E. ##STR69##

In step a6 of SCHEME 6, a compound of formula (II) in which --A-- is thedivalent radical --N(R₁)--CO--CO--and E is an O-protecting group,obtained in step g5 of SCHEME 5, is reduced. The reduction is effectedby means of a reducing agent such as lithium aluminum hydride, in aninert solvent such as an ether (for example tetrahydrofuran,1,2-dimethoxyethane or diethyl ether) or an aromatic solvent such astoluene, at a temperature between room temperature and the refluxtemperature of the solvent.

If appropriate, the O-protecting group is removed in step b6 by acidhydrolysis using the methods described above to give the compound offormula (II) in which E is hydrogen.

The compounds of formula (II) in which --A-- is the divalent radical--N(R₁)--CO-- and E is hydrogen or an O-protecting group are preparedaccording to SCHEME 7 below, in which m, R₁ and Ar₁ are as defined for acompound of formula (I) and Pr₁ is as defined in SCHEME 2 above.##STR70##

In step a7, the hydroxyl of the compound of formula (XXXII), obtained instep e5 of SCHEME 5, is protected by the methods known to those skilledin the art.

In step b7, the resulting compound of formula (XXXIII) is reacted with areactive derivative of carbonic acid, such as 1,1'-carbonyldiimidazole,phosgene in toluene, or p-nitrophenyl chloroformate, in the presence ofa base such as triethylamine, N,N-diisopropylethylamine orN-methylmorpholine, to give an expected compound of formula (II) inwhich E is an O-protecting group. The reaction is carried out in aninert solvent such as a chlorinated solvent (for example1,2-dichloroethane or dichloromethane), an ether (for exampletetrahydrofuran), an amide (for example N,N-dimethylformamide) or anaromatic solvent (for example toluene), at a temperature between -60° C.and 60° C.

If appropriate, a compound of formula (II) in which E is hydrogen isprepared in step c7 by the methods known to those skilled in the art.

The compounds of formula (II) in which --A-- is the divalent radical--O--CH₂ -- and E is hydrogen or an O-protecting group are preparedaccording to SCHEME 8 below, in which m and Ar₁ are as defined for acompound of formula (I) and Pr₂ is as defined in SCHEME 2 above.##STR71##

In step a8 of SCHEME 8, a compound of formula (XXVII) is reacted withaqueous formaldehyde solution in an inert solvent such astetrahydrofuran, at a temperature between room temperature and thereflux temperature of the solvent, to give a compound of the expectedformula (II) in which E is an O-protecting group.

Using the methods described above, the O-protecting group Pr₂ is removedby basic hydrolysis (step b8) to give the compound of formula (II) inwhich E is hydrogen.

The compounds of formulae (XVIII), (XIX), (XXIII), (XXIV), (XXVII),(XXXI), (XXX), (XXXII) and (XXXIII) and the compounds of formula(XXXIV), defined below, are novel products which constitute the keyintermediates for the preparation of the compounds of formula (I).

Thus the compounds of the formula ##STR72## in which m and Ar₁ are asdefined for a compound of formula (I);

E is as defined for a compound of formula (II); and

L is a cyano group or an aminomethyl group,

in enantiomerically pure form or in racemic form if L is an aminomethylgroup, are novel and form part of the invention.

The compounds of the formula ##STR73## in which: m, Ar₁, E and L are asdefined above; and

G is a hydrogen or an O-protecting group,

in enantiomerically pure form or in racemic form if L is an aminomethylgroup, are novel and form part of the invention.

The compounds of the formula ##STR74## in which m, Ar₁, E and L are asdefined above;

R₁ is as defined for a compound of formula (I); and

M is a hydrogen or an N-protecting group,

in enantiomerically pure form or in racemic form if L is an aminomethylgroup, are novel and form part of the invention.

The compounds of formulae (XXXV), (XXXVI) and (XXXVII) are obtained bythe methods described above. More particularly, the deprotectedcompounds (E═G═M═H) are obtained after removal of the O-protecting orN-protecting groups by the methods known to those skilled in the art.

Thus, according to another of its features, the present inventionrelates to compounds of the formula ##STR75## in which m and Ar₁ are asdefined for a compound of formula (I);

E is a hydrogen or an O-protecting group;

L is a cyano group or an aminomethyl group;

D is a group selected from: ##STR76## G is a hydrogen or an O-protectinggroup; M is a hydrogen or an N-protecting group; and

R₁ is as defined for a compound of formula (I),

in enantiomerically pure form or in racemic form if L is an aminomethylgroup.

The piperidines of formula (XI) are known or are prepared by knownmethods such as those described in EP-A-0428434, EP-A-0474561,EP-A-0512901 and EP-A-0515240.

The piperidines of formula (XI) can also be prepared by methods wellknown to those skilled in the art, such as those described in thefollowing publications:

J. Heterocyclic Chem., 1986, 23, 73-75

J. Chem. Soc., 1950, 1469

J. Chem. Soc., 1945, 917

J. Pharmaceutical Sci., 1972, 61, 1316-1317

J. org. Chem., 1957, 22, 1484-1489

Chem. Ber., 1975, 108, 3475-3482.

The compounds of formula (XI) are generally prepared in a form protectedon the piperidine nitrogen; the actual compounds of formula (XI) areobtained after a deprotection step.

More particularly, to prepare for example a compound of formula (XI) inwhich J'₁ is a group ##STR77## in which Ar₂ is a pyrid-2-yl radical, nis zero and R'₃ is a hydroxyl, 2-bromopyridine is reacted with1-benzylpiperid-4-one in the presence of a base such as butyllithium.The expected 4-hydroxy-4-(pyrid-2-yl)-piperidine is obtained afterremoval of the N-protecting group.

To prepare a compound of formula (XI) in which R'₃ is a group --NR₄ R₅in which R₄ and R₅ are each hydrogen, a compound of formula (XI) inwhich R'₃ is an acetamido group is hydrolyzed in an acid medium.

A compound of formula (XI) in which R'₃ is a group --NR₄ R₅ in which R₄and R₅, together with the nitrogen atom to which they are bonded, form aheterocycle is prepared by the application or adaptation of Bruylants'reaction (Bull. Soc. Chim. Belges, 1924, 33, 467 and TetrahedronLetters, 1988, 29 (52), 6827-6830).

To prepare a compound of formula (XI) in which R'₃ is a group --CH₂--NR₁₂ R₁₃ in which R₁₂ and R₁₃ are each hydrogen, a compound of formula(XI) in which R'₃ is a cyano is reduced. This reduction is effected bythe methods well known to those skilled in the art.

A compound of formula (XI) in which R'₃ is a group --CH₂ --CH₂ --NR₁₂R₁₃ in which R₁₂ and R₁₃ are each a hydrogen is prepared from a compoundof formula (XI) in which R'₃ is a group --CH₂ --CH₂ --OH by applicationor adaptation of the method described in J. Med. Chem., 1989, 32,391-396.

A compound of formula (XI) in which R'₃ is a group --NR₄ R₅ in which R₄is a hydrogen and R₅ is a (C₁ -C₇)-alkyl or, respectively, a (C₃-C₇)-cycloalkylmethyl or a benzyl can be prepared by reducing a compoundof formula (XI) in which R'₃ is a group --(CH₂)_(q) --NR₆ COR₇ in whichq is zero, R₆ is hydrogen and R₇ is a hydrogen or a (C₁ -C₆)-alkyl or,respectively, a (C₃ -C₇)-cycloalkyl or a phenyl. The reaction is carriedout by means of a reducing agent such as lithium aluminum hydride, in asolvent such as tetrahydrofuran, at the reflux temperature of thesolvent.

By an identical reaction, the compounds of formula (XI) in which R'₃ isa group --NR₄ R₅ in which R₄ is a (C₁ -C₇)-alkyl and R₅ is a (C₁-C₇)-alkyl or, respectively, a (C₃ -C₇)-cycloalkylmethyl or a benzyl canbe prepared from a compound of formula (XI) in which R'₃ is a group--(CH₂)_(q) --NR₆ COR₇ in which q is zero, R₆ is a (C₁ -C₇)-alkyl and R₇is a hydrogen or a (C₁ -C₆)-alkyl or, respectively, a (C₃-C₇)-cycloalkyl or a phenyl.

Likewise, the compounds of formula (XI) in which R'₃ is a group --CH₂--NR₁₂ R₁₃ or, respectively, --CH₂ CH₂ NR₁₂ R₁₃ in which R₁₂ is ahydrogen or a (C₁ -C₇)-alkyl and R₁₃ is a (C.sub. -C₇)-alkyl, a (C₃-C₇)-cycloalkylmethyl or a benzyl can be prepared from a compound offormula (XI) in which R'₃ is a group --(CH₂)_(q) --NR₆ COR₇ in which qis respectively 1 or 2, R₆ is a hydrogen or a (C₁ -C₇)-alkyl and R₇ is ahydrogen, a (C₁ -C₆)-alkyl, a (C₃ -C₇)-cycloalkyl or a phenyl.

A compound of formula (XI) in which R'₃ is a group --(CH₂)_(q) --NR₆COR₇ in which R₆ and R₇ together are a group --(CH₂)₃ -- or --(CH₂)₄ --is prepared by application or adaptation of the method described in J.Med. Chem., 1985, 28, 46-50.

The compounds of formula (XI) in which R'₃ is a group --(CH₂)_(q) --NR₆C(═W₁)R₇ in which W₁ is an oxygen atom, q is 0, 1 or 2, R₆ is a hydrogenor a (C₁ -C₇)-alkyl and R₇ is a hydrogen or, respectively, a (C₁-C₇)-alkyl, a phenyl, a benzyl, a pyridyl, an optionally substituted (C₃-C₇)-cycloalkyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl areobtained by reacting formic acid in acetic anhydride or, respectively,the appropriate anhydride (R₇ CO)₂ O or the appropriate acid chloride R₇COCl, in the presence of a base such as triethylamine, with a compoundof formula (XI) in which R'₃ is a group --NHR₆, --CH₂ --NHR₆ or --CH₂--CH₂ --NHR₆.

Likewise, it is obvious for those skilled in the art that the compoundsof formula (XI) in which R'₃ is a group --(CH₂)_(q) --NR₆ --C(═W₁)R₇ inwhich q, R₆ and W₁ are as defined above and R₇ is a vinyl group may beprepared by reaction with an acryloyl chloride.

Likewise, the compounds of formula (XI) in which R'₃ is a group--(CH₂)_(q) --NR₆ COOR₈ are prepared by reaction of a compound offormula (XI) in which R'₃ is a group --NHR₆, --CH₂ --NHR₆ or --CH₂ --CH₂--NHR₆ in the presence of a base such as triethylamine, with achloroformate of the formula ClCOOR₈.

The compounds of formula (XI) in which R'₃ is a group --(CH₂)_(q) --NR₆SO₂ R₉ are prepared by reaction of a compound of formula (XI) in whichR'₃ is a group --NHR₆, --CH₂ --NHR₆ or --CH₂ --CH₂ --NHR₆ in thepresence of a base such as triethylamine, with a sulfonyl chloride ofthe formula ClSO₂ R₉.

The compounds of formula (XI) in which R'₃ is a group --(CH₂)_(q) --NR₆C(═W₁)NR₁₀ R₁₁ in which R₁₀ is a hydrogen and W₁ is an oxygen atom areprepared by reaction of a compound of formula (XI) in which R'₃ is agroup --NHR₆, --CH₂ --NHR₆ or --CH₂ --CH₂ --NHR₆ in the presence of abase such as triethylamine, with an isocyanate of the formula R₁₁ N═C═O.

The compounds of formula (XI) in which R'₃ is a group --(CH₂)_(q) --NR₆C(═W₁)NR₁₀ R₁₁ in which R₁₀ is a (C₁ -C₇)-alkyl and W₁ is an oxygen atomare prepared by reaction of a compound of formula (XI) in which R'₃ is agroup --NHR₆, --CH₂ --NHR₆ or --CH₂ --CH₂ --NHR₆ in the presence of abase such as triethylamine, with a carbamoyl chloride of the formulaClCONR₁₀ R₁₁.

A compound of formula (XI) in which R'₃ is a group --(CH₂)_(q) --NR₆CONR₁₀ R₁₁ can also be obtained by reacting a compound HNR₁₀ R₁₁ with acompound of formula (XI) in which R'₃ is a group --(CH₂)_(q) --NR_(COOR)₈ in which R₈ is a phenyl.

A compound of formula (XI) in which R'₃ is a group --(CH₂)_(q) --NR₆COOR₈ in which q=0 and R₆ is hydrogen can also be prepared by reacting acompound R₈ OH with a compound of formula (XI) in which R'₃ is anisocyanato group, --N═C═O.

A compound of formula (XI) in which R'₃ is a group --(CH₂)_(q) --NR₆CONR₁₀ R₁₁ in which q=0 and R₆ is hydrogen can also be prepared byreacting a compound NHR₁₀ R₁₁ with a compound of formula (XI) in whichR'₃ is an isocyanato group.

A compound of formula (XI) in which R'₃ is an isocanato group isprepared from a compound of formula (XI) in which R'₃ is a carboxyl bythe method described in Organic Synthesis, 51, 48-52.

A compound of formula (XI) in which R'₃ is a group --(CH₂)_(q) --NR₆C(═W₁)R₇ in which W₁ is a sulfur atom is obtained from a correspondingcompound of formula (XI) which is protected on the piperidine nitrogenand in which W₁ is an oxygen atom by reaction with phosphoruspentasulfide or Lawesson's reagent,2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide,followed by deprotection of the piperidine nitrogen.

A compound of formula (XI) in which R'₃ is a group --(CH₂)_(q) --NR₆C(═W₁)NR₁₀ R₁₁ in which W₁ is a sulfur atom is prepared by reacting acompound of formula (XI) which is protected on the piperidine nitrogenand in which R'₃ is a group --(CH₂)_(q) --NR₆ CONR₁₀ R₁₁ with phosphoruspentasulfide or Lawesson's reagent.

A compound of formula (XI) in which R'₃ is a group --(CH₂)_(q) --OH inwhich q is respectively one or two is prepared by reducing a compound offormula (XI) in which R'₃ is respectively a methoxycarbonyl or amethoxycarbonylmethyl by the method described in Chem. Ber., 1975, 108,3475-3482.

The compounds of formula (XI) in which R'₃ is a group --(CH₂)_(q)--OCOR₁₇ are obtained by reacting an acid chloride R₁₇ COCl with thecompounds of formula (XI) in which R'₃ is a group --(CH₂)_(q) --OH, inthe presence of a base such as triethylamine; the compounds of formula(XI) in which R'₃ is a group HCOO--(CH₂)_(q) -- are obtained by reactionwith formic acid.

The compounds of formula (XI) in which R'₃ is a group (C₁-C₇)-alkyl--NHCOO--(CH₂)_(q) -- are obtained by reacting a carbamoylchloride (C₁ -C₇)-alkyl--NHCOCl with the compounds of formula (XI) inwhich R'₃ is a group --(CH₂)_(q) --OH.

The same compounds are prepared by reacting an isocyanate (C₁-C₇)-alkyl--N═C═O with the compounds of formula (XI) in which R'₃ is agroup --(CH₂)_(q) --OH.

A compound of formula (XI) in which R'₃ is a carboxyl can be prepared byhydrolyzing a compound of formula (XI) in which R'₃ is a cyano by themethods known to those skilled in the art.

A compound of formula (XI) in which R'₃ is a carboxymethyl can beprepared by the method described in Chem. Ber., 1975, 108, 3475-3482.

A compound of formula (XI) in which R'₃ is respectively a (C₁-C₇)-alkoxycarbonyl or a (C₁ -C₇)-alkoxycarbonylmethyl can be preparedfrom a compound of formula (XI) in which R'₃ is respectively a carboxylor a carboxymethyl by means of an esterification reaction using themethods well known to those skilled in the art.

To prepare a compound of formula (XI) in which J'₁ is a group ##STR78##in which Ar₂ is an optionally substituted phenyl radical, n is one andR'₃ is a (C₁ -C₇)-alkoxycarbonyl, a protected 4-(C₁-C₇)-alkoxycarbonylpiperidine is reacted with an optionally substitutedbenzyl halide in the presence of a base such as sodium hydride,potassium tert-butylate or sodium diisopropylamide, in a solvent such astetrahydrofuran, N,N-dimethylformamide or dimethyl sulfoxide, at atemperature between -78° C. and room temperature. The compound of theexpected formula (XI) is obtained after a deprotection step.

To prepare a compound of formula (XI) in which R'₃, is respectively agroup --CONR₁₀ R₁₁ or a group --CH₂ CONR₁₀ R₁₁, a compound of formula(XI) in which R'₃, is respectively a carboxyl or a carboxymethyl isreacted with a compound of the formula HNR₁₀ R₁₁ by the methods wellknown to those skilled in the art.

Using the methods cited above, a compound of formula (XI) in which R'₃is a group --C(═W₁)NR₁₀ R₁₁ or a group --CH₂ --C(═W₁)NR₁₀ R₁₁ in whichW₁ is a sulfur atom is prepared from a compound of the correspondingformula (XI) in which W₁ is an oxygen atom.

To prepare a compound of formula (XI) in which R'₃ is a group ##STR79##in which R₂₄ and R₂₅ are each independently a hydrogen or a (C₁-C₇)-alkyl, a compound of formula (XI) in which R'₃ is a group ##STR80##in which Hal is a halogen atom, preferably bromine, is reacted with athiourea in which one of the amino groups is free or substituted by oneor two (C₁ -C₇)-alkyls.

A compound of formula (XI) in which R'₃ is a group ##STR81## in whichR₂₅ is a formyl or, respectively, a (C₁ -C₇)-alkylcarbonyl is preparedby reacting formic acid in acetic anhydride or, respectively, an acidchloride (C₁ -C₇)-alkyl-COCl, in the presence of a base such astriethylamine, with the above compound of formula (XI) which isprotected on the piperidine nitrogen and in which R₂₅ is hydrogen. Theexpected compound is obtained after a deprotection step.

The compound of formula (XI) in which R'₃ is a group ##STR82## in whichHal is a bromine atom is obtained by brominating a compound of formula(XI) in which R'₃ is a group --CO--CH₂ --R₂₃ by the conventionalmethods.

A compound of formula (XI) in which J'₁ is a group ##STR83## in whichR₁₄ is a group --CONR ₁₅ R₁₆ and R'₃ is hydrogen can be prepared byreacting a protected 4-carboxypiperidine with a compound of the formulaHNR₁₅ R₁₆ by the methods well known to those skilled in the art. Thecompound of the expected formula (XI) is obtained after a deprotectionstep.

To prepare a compound of formula (XI) in which J'₁ is a group ##STR84##in which R₁₄ is a group --NR₁₅ R₁₆ and R'₃ is a cyano, a Streckerreaction is carried out by reacting a 1-benzylpiperid-4-one with acompound of the formula HNR₁₅ R₁₆ in the presence of sodium cyanide. Thecompound of the expected formula (XI) is obtained after a deprotectionstep.

A compound of formula (XI) in which R'₃ is a group --O--CH₂ --CH₂ --OR₁₈in which R₁₈ is hydrogen can be prepared by reacting a compound offormula (XI) in which R'₃ is a benzoyloxy with ethylene glycol in thepresence of an acid such as sulfuric acid.

The compounds of formula (XI) in which R'₃ is a group --O--CH₂ --CH₂--OR₁₈ in which R₁₈ is a (C₁ -C₇)-alkyl are prepared by means of anidentical reaction using a 2-(C₁ -C₇)-alkoxyethanol.

The compounds of formula (XI) in which R'₃ is a group --O--CH₂ CH₂--OR₁₈ in which R₁₈ is a formyl are prepared by reacting formic acidwith a compound of formula (XI) in which R'₃ is a group --O--CH₂ CH₂--OH. The compounds of formula (XI) in which R'₃ is a group --O--CH₂ CH₂--OR₁₈ in which R₁₈ is a (C₁ -C₇)-alkylcarbonyl are prepared by reactionwith a C₂ -C₈ acid chloride in the presence of a base such astriethylamine.

A compound of formula (XI) in which R'₃ is a group --NR₆ COCOR₁₉ inwhich R₁₉ is a (C₁ -C₄)-alkoxy is prepared by reacting a compound of theformula ClCOCOR₁₉ with a compound of formula (XI) in which R'₃ is agroup --NHR₆.

A compound of formula (XI) in which R'₃ is a group --CO--NR₂₀ --NR₂₁ R₂₂is prepared by reacting a compound HNR₂₀ --NR₂₁ R₂₂ with a compound offormula (XI) in which R'₃ is a chloroformyl.

A compound of formula (XI) in which R'₃ is a group ##STR85## can beprepared by reacting a protected compound of formula (XI) in which R'₃is a carbazoyl group (--CONH--NH₂) with cyanogen bromide by the methoddescribed in J. Org. Chem., 1961, 26, 88-95. The compound of formula(XI) in which R'₃ is a carbazoyl group is obtained by reacting hydrazinewith a compound of formula (XI) in which R'₃ is a chloroformyl, which isitself obtained by reacting thionyl chloride with a compound of formula(XI) in which R'₃ is a carboxyl.

The piperidines of formula (XII) are known or are prepared by knownmethods.

The quinuclidines of formula (XIII) are known or are prepared by knownmethods such as those described by T. Perrine, J. Org. Chem., 1957, 22,1484-1489.

The pyridines of formula (XIV) are known or are prepared by knownmethods.

The enantiomers of the compounds according to the invention, of theformula ##STR86## in which "*" denotes that the carbon atom carryingthis label has the determined (+) or (-) absolute configuration; and

Am, m, Ar₁, A and T are as defined for the compounds of formula (I),

and the salts thereof, where appropriate, with mineral or organic acids,are novel compounds which form part of the invention.

Resolution of the racemic mixtures of the compounds of formula (I) makesit possible to isolate the enantiomers of formula (I*).

It is preferable, however, to resolve the racemic mixtures from acompound of formula (II) or an intermediate which is useful for thepreparation of a compound of formula (II).

Thus, if it is desired to prepare the enantiomers (I*) of the compoundsof formula (I) in which --A-- is the divalent radical --CH₂ --O--CO--,the racemic mixture of an intermediate of the formula ##STR87## in whichm and Ar₁ are as defined for a compound of formula (I), which isobtained by removal of the O-protecting group Pr from a compound offormula (XIX) by the methods described above, is resolved.

If it is desired to prepare the enantiomers (I*) of the compounds offormula (I) in which --A-- is the divalent radical --O--CO--, --O--CH₂--CO--, --O--CH₂ --CH₂ --, or --O--CH₂ --, the racemic mixture of anintermediate of the formula ##STR88## in which m and Ar₁ are as definedfor a compound of formula (I) and Pr₂ is as defined in SCHEME 2 above,is resolved.

If it is desired to prepare the enantiomers (I*) of the compounds offormula (I) in which --A-- is the divalent radical --O--CH₂ --CH₂ --, itis also possible to resolve the racemic mixture of a compound of theformula ##STR89## in which m and Ar₁ are as defined for a compound offormula (I).

If it is desired to prepare the enantiomers (I*) of the compounds offormula (I) in which --A-- is the divalent radical --N(R₁)--CO--,--N(R₁)--CO--CO-- or --N(R₁)--CH₂ --CH₂ --, the racemic mixture of anintermediate of the formula ##STR90## in which m, Ar₁ and R₁ are asdefined for a compound of formula (I), is resolved.

If resolution of the racemates is effected on the intermediates offormula (XXXIV), (XXVII), (XXXII) or (II) [--A--═--O--CH₂ --CH₂ -- andE═H], this can be done by known methods involving the formation of asalt with optically active acids, for example with (+)- or (-)-tartaricacid. The diastereoisomers are then separated by conventional methodssuch as crystallization or chromatography, after which the opticallypure enantiomers are obtained by hydrolysis.

The compounds of formula (I) above also include those in which one ormore hydrogen, carbon or iodine atoms have been replaced with theirradioactive isotope, for example tritium, carbon-14 or iodine-125. Suchlabeled compounds are useful in research, metabolic or pharmacokineticstudies and in biochemical tests as receptor ligands.

The affinity of the compounds for the tachykinin receptors was evaluatedin vitro by several biochemical tests using radioligands:

1) The binding of [¹²⁵ I]BH-SP (substance P labeled with iodine-125using Bolton-Hunter's reagent) to the NK₁ receptors of humanlymphoblasts.

2) The binding of [¹²⁵ I]His-NK_(A) to the NK₂ receptors of the ratduodenum or bladder.

3) The binding of [¹²⁵ I]His[MePhe⁷ ]NK_(B) to the NK₃ receptors of therat cerebral cortex, the guinea-pig cerebral cortex and the gerbilcerebral cortex, and to the human NK₃ cloned receptors expressed by CHOcells (Buell et al., FEBS Letters, 1992, 299, 90-95).

The tests were performed according to X. Emonds-Alt et al. (Eur. J.Pharmacol., 1993, 250, 403-413).

The compounds according to the invention have an affinity for theabovementioned tachykinin receptors, with an inhibition constant Kibelow 10⁻⁸ M.

In particular, the compounds of the present invention are activeprinciples of pharmaceutical compositions, the toxicity of which iscompatible with their use as drugs.

The compounds of the present invention are generally administered indosage units. Said dosage units are preferably formulated aspharmaceutical compositions in which the active principle is mixed witha pharmaceutical excipient.

Thus, according to another of its features, the present inventionrelates to pharmaceutical compositions in which a compound of formula(I) or a pharmaceutically acceptable salt thereof is present as theactive principle.

The compounds of formula (I) above and the pharmaceutically acceptablesalts thereof can be used in daily doses of 0.01 to 100 mg per kilogramof body weight of the mammal to be treated, preferably in daily doses of0.1 to 50 mg/kg. In humans, the dose can preferably vary from 0.5 to4000 mg per day, more particularly from 2.5 to 1000 mg, depending on theage of the subject to be treated or the type of treatment: prophylacticor curative.

In the pharmaceutical compositions of the present invention for oral,sublingual, inhalational, subcutaneous, intramuscular, intravenous,transdermal, local or rectal administration, the active principles canbe administered to animals and humans in unit forms of administration,mixed with conventional pharmaceutical carriers. The appropriate unitforms of administration include oral forms such as tablets, gelatincapsules, powders, granules and solutions or suspensions to be takenorally, sublingual and buccal forms of administration, aerosols,implants, subcutaneous, intramuscular, intravenous, intranasal orintraocular forms of administration and rectal forms of administration.

When a solid composition in the form of tablets is prepared, the mainactive principle is mixed with a pharmaceutical vehicle such as silica,gelatin, starch, lactose, magnesium stearate, talc, gum arabic or thelike. The tablets can be coated with sucrose, various polymers or otherappropriate substances or else they can be treated so as to have aprolonged or delayed activity and so as to release a predeterminedamount of active principle continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive principle with a diluent such as a glycol or a glycerol ester,and incorporating the mixture obtained into soft or hard gelatincapsules.

A preparation in the form of a syrup or elixir can contain the activeprinciple together with a sweetener, which is preferably calorie-free,methylparaben and propylparaben as an antiseptic, a flavoring and anappropriate color.

The water-dispersible granules or powders can contain the activeprinciple mixed with dispersants or wetting agents or with suspendingagents such as polyvinylpyrrolidone, as well as with sweeteners or tastecorrectors.

Rectal administration is effected using suppositories, which areprepared with binders melting at the rectal temperature, for examplecocoa butter or polyethylene glycols.

Parenteral, intranasal or intraocular administration is effected usingaqueous suspensions, isotonic saline solutions or sterile and injectablesolutions which contain pharmacologically compatible dispersants and/orwetting agents, for example propylene glycol or butylene glycol.

Administration by inhalation is effected using an aerosol which containsfor example sorbitan trioleate or oleic acid, as well astrichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethaneor any other biologically compatible propellant gas; it is also possibleto use a system containing the active principle in powder form, byitself or associated with an excipient.

The active principle can also be formulated as microcapsules, with oneor more carriers or additives if appropriate.

In each dosage unit, the active principle of formula (I) is present inthe amounts appropriate to the daily doses envisaged. In general, eachdosage unit is suitably adjusted according to the dosage and theintended type of administration, for example tablets, gelatin capsulesand the like, sachets, ampoules, syrups and the like, and drops, so thatsuch a dosage unit contains from 0.5 to 1000 mg of active principle,preferably from 2.5 to 250 mg, to be administered one to four times aday.

The abovementioned compositions can also contain other active productssuch as, for example, bronchodilators, antitussives, antihistamines,anti-inflammatories, antiemetics and chemotherapeutic agents.

According to another of its features, the present invention relates tothe use of the products of formula (I) for the preparation of drugsintended for the treatment of physiological disorders associated with anexcess of tachykinins, and all neurokinin-dependent pathologicalconditions of the respiratory, gastrointestinal, urinary, immune,cardiovascular and central nervous systems, as well as pain andmigraine.

Non-limiting examples are:

acute and chronic pain associated for example with migraine, with painsexperienced by cancer and angina patients, and with chronic inflammatoryprocesses such as osteoarthritis and rheumatoid arthritis,

inflammations such as neurogenic inflammations, chronic inflammatorydiseases, for example obstructive chronic respiratory diseases, asthma,allergies, rhinitis, coughs, bronchitis, hypersensitivity, for exampleto pollen and mites, rheumatoid arthritis, fibrositis, osteoarthritis,psoriasis, ulcerative colitis, Crohn's disease, inflammation of theintestines (irritable colon), prostatitis, nervous bladder,incontinence, cystitis, urethritis and nephritis, ophthalmic diseasessuch as conjunctivitis and vitreo-retinopathy, and skin diseases such ascontact dermatitis, atopical dermatitis, urticaria, eczema, pruritus andburns, especially sunburn,

diseases of the immune system associated with suppression or stimulationof the functions of the immune cells, for example rheumatoid arthritis,psoriasis, Crohn's disease, diabetes, lupus and rejection reactionsfollowing transplantation,

small-cell lung cancers and demyelination diseases such as multiplesclerosis or amyotrophic lateral sclerosis,

diseases of the central nervous system of the neuropsychiatric orneurological type, such as anxiety, vigilance disorders, mood disorders,depression, psychosis, schizophrenia, mania, dementia, epilepsy,Parkinson's disease, Alzheimer's disease, drug dependence, alcoholism,Down's syndrome and Huntington's chorea, as well as neurodegenerativediseases and stress-related somatic disorders,

diseases of the gastrointestinal system, such as nausea, vomiting of anyorigin, irritable colon, gastric and duodenal ulcers, esophageal ulcer,diarrhea and hypersecretions,

diseases of the cardiovascular system, such as hypertension, thevascular aspects of migraine, edema, thrombosis, angina pectoris,vascular spasms, circulatory diseases due to vasodilation, Reynauld'sdiseases, fibrosis and collagen diseases, and

heart rate and rhythm disorders, in particular those caused by pain orstress.

The present invention also includes a method of treating said complaintsat the doses indicated above.

The following abbreviations are used in the Preparations and in theExamples:

Me, OMe: methyl, methoxy

Et, OEt: ethyl, ethoxy

EtOH: ethanol

MeOH: methanol

Ether: diethyl ether

Iso ether: diisopropyl ether

DMF: dimethylformamide

DMSO: dimethyl sulfoxide

DCM: dichloromethane

THF: tetrahydrofuran

AcOEt: ethyl acetate

Na₂ CO₃ : sodium carbonate

NaHCO₃ : sodium hydrogencarbonate

NaCl: sodium chloride

Na₂ SO₄ : sodium sulfate

MgSO₄ : magnesium sulfate

NaOH: sodium hydroxide

HCl: hydrochloric acid

TFA: trifluoroacetic acid

KCN: potassium cyanide

Na₂ S₂ O₅ : sodium metabisulfite

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

NH₄ Cl: ammonium chloride

M.p.: melting point

RT: room temperature

Silica H: silica gel 60H, marketed by Merck (DARMSTADT)

NMR: nuclear magnetic resonance

δ: chemical shift

s: singlet

bs: broad singlet

d: doublet

t: triplet

q: quadruplet

mt: multiplet

U: unresolved signals

PREPARATIONS Preparation 1.15-(3,4-Dichlorophenyl)-5-[2-(tetrahydropyran-2-yloxy)ethyl]tetrahydro-2H-1,3-oxazin-2-one

A) 2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butanenitrile

A suspension of 17.75 g of sodium hydride (80% dispersion in oil) in 750ml of THF is cooled in an ice bath, a solution of 100 g of3,4-dichlorophenylacetonitrile in 250 ml of THF is added dropwise andthe reaction mixture is stirred for two hours at RT. It is cooled to-20° C., a solution of 112.36 g of1-bromo-2-(tetrahydropyran-2-yloxy)ethane in 120 ml of THF is addeddropwise and the reaction mixture is stirred for 2 hours at RT. It isconcentrated under vacuum, the residue is taken up with water andextracted with ether, the organic phase is washed twice with a buffersolution of pH 4, with a buffer solution of pH 7 and twice withsaturated NaCl solution and dried over Na₂ SO₄ and the solvent isevaporated off under vacuum. The residue is chromatographed on silicausing toluene and then a toluene/AcOEt mixture (100/3; v/v) as theeluent to give 113.5 g of the expected product, which is used as such.

B)2-(3,4-Dichlorophenyl)-2-(hydroxymethyl)-4-(tetrahydropyran-2-yloxy)butanenitrile

A mixture of 12.56 g of the compound obtained in the previous step, 9.6g of 37% aqueous formaldehyde solution and 0.3 g of DBU in 25 ml of1,2-dimethoxyethane is refluxed for 1 hour. The reaction mixture isconcentrated under vacuum, the residue is extracted with ether, theorganic phase is washed twice with water, twice with a buffer solutionof pH 4, twice with water and twice with saturated NaCl solution anddried over Na₂ SO₄ and the solvent is evaporated off under vacuum togive 17 g of the expected product, which is used as such.

C)2-(3,4-Dichlorophenyl)-2-(hydroxymethyl)-4-(tetrahydropyran-2-yloxy)butylamine

A mixture of 17 g of the compound obtained in the previous step and 6 gof Raney® nickel in 300 ml of EtOH and 40 ml of 20% aqueous ammoniasolution is hydrogenated for 5 hours at 40° C. and at atmosphericpressure. The catalyst is filtered off and the filtrate is concentratedunder vacuum. The residue is taken up with DCM, the organic phase iswashed with water and with saturated NaCl solution and dried over MgSO₄and the solvent is evaporated off under vacuum to give 16.5 g of theexpected product in the form of an oil, which is used as such.

D)5-(3,4-Dichlorophenyl)-5-[2-(tetrahydropyran-2-yloxy)ethyl]tetrahydro-2H-1,3-oxazin-2-one

24.6 g of a 20% solution of phosgene in toluene, diluted in 150 ml ofDCM, are cooled to -70° C., a solution of 16.5 g of the compoundobtained in the previous step and 5.7 g of triethylamine in 100 ml ofDCM is added dropwise and the reaction mixture is stirred while thetemperature is allowed to rise to RT. It is concentrated under vacuum,the residue is taken up with a water/AcOEt mixture and the product whichcrystallizes at the interphase is wrung to give a first crop of theexpected product. After decantation of the filtrate, the organic phaseis washed with water, with a buffer solution of pH 4 and with saturatedNaCl solution and dried over MgSO₄ and the solvent is evaporated offunder vacuum. The residue is taken up with AcOEt and the crystallineproduct formed is wrung to give the second crop of the product. A totalof 4.5 g of the expected product is obtained.

Preparation 1.25-(3,4-Dichlorophenyl)-5-[3-(tetrahydropyran-2-yloxy)propyl]tetrahydro-2H-1,3-oxazin-2-one

A) 2-(3,4-Dichlorophenyl)-5-(tetrahydropyran-2-yloxy)pentanenitrile

A solution of 50.8 g of 3,4-dichlorophenylacetonitrile in 250 ml of THFis added dropwise at a temperature below 20° C. to a suspension of 12 gof sodium hydride (55% dispersion in oil) in 175 ml of THF and thereaction mixture is stirred for 2 hours at RT. It is cooled to -20° C.,a solution of 62.5 g of 1-bromo-3-(tetrahydropyran-2-yloxy)propane in 60ml of THF is added dropwise and the reaction mixture is stirred whilethe temperature is allowed to rise to RT. It is poured into a solutionof 31 g of ammonium chloride in 1.4 liters of water and extracted withether, the combined organic phases are washed with saturated NaClsolution and dried over MgSO₄ and the solvents are evaporated off undervacuum. The residue is chromatographed on silica using toluene and thena toluene/AcOEt mixture (95/5; v/v) as the eluent to give 64 g of theexpected product, which is used as such.

B)2-(3,4-Dichlorophenyl)-2-(hydroxymethyl)-5-(tetrahydropyran-2-yloxy)pentanenitrile

A mixture of 15 g of the compound obtained in the previous step, 11.2 gof 37% aqueous formaldehyde solution and 0.35 g of DBU in 30 ml of1,2-dimethoxyethane is refluxed for 1 hour. The reaction mixture isconcentrated under vacuum, the residue is extracted with ether, theorganic phase is washed with water, twice with a buffer solution of pH4, twice with water and twice with saturated NaCl solution and driedover Na₂ SO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica using toluene and then a toluene/AcOEtmixture (80/20; v/v) as the eluent to give 15.5 g of the expectedproduct, which is used as such.

C)2-(3,4-Dichlorophenyl)-2-(hydroxymethyl)-5-(tetrahydropyran-2-yloxy)pentylamine

A mixture of 15.5 g of the compound obtained in the previous step and 5g of Raney® nickel in 200 ml of EtOH and 40 ml of 20% aqueous ammoniasolution is hydrogenated for 5 hours at 30° C. and at atmosphericpressure. The catalyst is filtered off and the filtrate is concentratedunder vacuum. The residue is taken up with DCM, the organic phase iswashed with water and with saturated NaCl solution and dried over MgSO₄and the solvent is evaporated off under vacuum to give 14.9 g of theexpected product in the form of an oil, which is used as such.

D)5-(3,4-Dichlorophenyl)-5-[3-(tetrahydropyran-2-yloxy)propyl]tetrahydro-2H-1,3-oxazin-2-one

21.4 g of a 20% solution of phosgene in toluene, diluted in 120 ml ofDCM, are cooled to -70° C., a solution of 14.9 g of the compoundobtained in the previous step and 4.98 g of triethylamine in 80 ml ofDCM is added dropwise and the reaction mixture is stirred while thetemperature is allowed to rise to RT. It is concentrated under vacuum,the residue is taken up with water and extracted with ether, the organicphase is washed with water and with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum to give 12.5 gof the expected product, which is used as such.

Preparation 1.36-(3,4-Dichlorophenyl)-6-[2-(tetrahydropyran-2-yloxy)ethyl]morpholin-3-one

A) 2-(3,4-Dichlorophenyl)-2-hydroxyacetonitrile

A mixture of 70 g of 3,4-dichlorobenzaldehyde and 90 g of Na₂ S₂ O₅ in300 ml of water is stirred overnight at RT. The reaction mixture iscooled to 0° C., a solution of 52 g of KCN in 100 ml of water is addeddropwise and the reaction mixture is stirred while the temperature isallowed to rise to RT. It is extracted with ether, the organic phase iswashed with water and dried over Na₂ SO₄ and the solvent is evaporatedoff under vacuum to give 76 g of the expected product, which is used assuch.

B) 2-(3,4-Dichlorophenyl)-2-(tetrahydropyran-2-yloxy)-acetonitrile

A solution of 76 g of the compound obtained in the previous step and0.25 g of p-toluenesulfonic acid monohydrate in 300 ml of DCM is cooledto 0° C., a solution of 39 g of 3,4-dihydro-2H-pyran in 50 ml of DCM isadded dropwise and the reaction mixture is stirred while the temperatureis allowed to rise to RT. It is washed with saturated NaHCO₃ solutionand with water, the organic phase is dried over Na₂ SO₄ and the solventis evaporated off under vacuum to give 33 g of the expected productafter crystallization at 0° C. from pentane. M.p.=61° C.

C)4-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)butanenitrile

56 ml of a 2 M solution of lithium diisopropylamide in THF are cooled to-60° C., a solution of 32 g of the compound obtained in the previousstep in 50 ml of THF is added dropwise and the mixture is stirred for 1hour at -60° C. A solution of 25.4 g of 2-bromoethyl benzoate in 50 mlof THF is then added dropwise at -60° C. and the reaction mixture isstirred while the temperature is allowed to rise to RT. It isconcentrated under vacuum, the residue is extracted with ether, theorganic phase is washed with water and with a buffer solution of pH 4and dried over Na₂ SO₄ and the solvent is evaporated off under vacuum.The residue is chromatographed on silica using a toluene/AcOEt mixture(100/5; v/v) as the eluent to give 34 g of the expected product, whichis used as such.

D)4-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)butylamine

A mixture of 34 g of the compound obtained in the previous step and 10 gof Raney® nickel in 400 ml of EtOH and 40 ml of concentrated ammoniasolution is hydrogenated at RT and at atmospheric pressure. The catalystis filtered off and the filtrate is concentrated under vacuum. Theresidue is taken up with water and extracted with ether, the organicphase is washed with saturated NaCl solution and dried over Na₂ SO₄ andthe solvent is evaporated off under vacuum. The residue ischromatographed on silica H using a gradient of a DCM/MeOH mixture (from100/1; v/v to 100/3; v/v) as the eluent to give 16 g of the expectedproduct, which is used as such.

E)N-(2-Bromoacetyl)-4-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxybutylamine

A solution of 16 g of the compound obtained in the previous step and 4.8g of triethylamine in 100 ml of DCM is cooled to -60° C., a solution of5.68 g of bromoacetyl chloride in 20 ml of DCM is added dropwise and thereaction mixture is stirred for 30 minutes. It is concentrated undervacuum, the residue is extracted with ether, the organic phase is washedwith water and with a buffer solution of pH 4 and dried over Na₂ SO₄ andthe solvent is evaporated off under vacuum. The product obtained isdissolved in the minimum amount of MeOH and acidified to pH 1 by theaddition of a saturated solution of gaseous HCl in ether, and thesolvents are evaporated off under vacuum. The residue is taken up withwater and extracted with AcOEt, the organic phase is washed withsaturated NaHCO₃ solution and with water and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum to give 16 g of the expectedproduct, which is used as such.

F) 6-(3,4-Dichlorophenyl)-6-(2-hydroxyethyl)morpholin-3-one

A mixture of 16 g of the compound obtained in the previous step, 50 mlof propan-2-ol, 15 ml of 10 N NaOH solution and 10 ml of DMF is stirredfor 4 hours. The reaction mixture is concentrated under vacuum, theresidue is extracted with AcOEt, the organic phase is washed with waterand dried over Na₂ SO₄ and the solvent is evaporated off under vacuum.The residue is chromatographed on silica H using a gradient of aDCM/MeOH mixture (from 100/3; v/v to 100/5; v/v) as the eluent to give6.1 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.05 ppm: mt: 2H 3.0 to 4.4ppm: u: 6H 4.5 ppm: t: 1H 7.3 to 8.3 ppm: u: 4H

G)6-(3,4-Dichlorophenyl)-6-[2-(tetrahydropyran-2-yloxy)ethyl]morpholin-3-one

A solution of 1.7 g of the compound obtained in the previous step and0.003 g of p-toluenesulfonic acid monohydrate in 50 ml of DCM is cooledto 0° C., 0.588 g of 3,4-dihydro-2H-pyran in 10 ml of DCM is addeddropwise and the reaction mixture is stirred for 1 hour at RT. It isconcentrated under vacuum, the residue is extracted with ether, theorganic phase is washed with saturated NaHCO₃ solution and with waterand dried over Na₂ SO₄ and the solvent is evaporated off under vacuum.The residue is chromatographed on silica H using a DCM/MeOH mixture(100/2; v/v) as the eluent to give 1.8 g of the expected product, whichis used as such.

Preparation 1.46-[2-(Benzoyloxy)ethyl]-6-(3,4-dichlorophenyl)morpholin-3-one

A mixture of 4.8 g of the compound obtained in step E of Preparation 1.3and 1.4 g of K₂ CO₃ in 100 ml of xylene is heated at 130° C. overnight.After cooling to RT, the reaction mixture is filtered and the filtrateis concentrated under vacuum. The residue is extracted with ether, theorganic phase is washed with a buffer solution of pH 2 and with waterand dried over MgSO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica H using a DCM/MeOH mixture (100/1;v/v) as the eluent to give 1.4 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.45 ppm: mt: 2H 3.75 ppm:AB system: 2H 3.9 to 4.5 ppm: u: 4H 7.4 to 7.9 ppm: u: 8H 8.25 ppm: bs:1H

This compound can also be obtained by following the three steps of themethod described below.

A') 4-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxybutylaminehydrochloride

This compound is described in step A of Preparation 1.7.

B')N-(2-Chloroacetyl)-4-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxybutylamine

A solution of 20 g of the compound obtained in the previous step and10.3 g of triethylamine in 100 ml of DCM is cooled to 0° C., 5.8 g ofchloroacetyl chloride are added dropwise and the reaction mixture isstirred for 30 minutes. It is concentrated under vacuum, the residue isextracted with AcOEt, the organic phase is washed with water, with abuffer solution of pH 2 and with water and dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 22 g of the expectedproduct, which is used as such.

C') 6-[2-(Benzoyloxy)ethyl]-6-(3,4-dichlorophenyl)morpholin-3-one

A solution of 22 g of the compound obtained in the previous step in 600ml of THF is cooled to -10° C., 11.42 g of potassium tert-butylate areadded and the reaction mixture is stirred until dissolution is complete.It is concentrated under vacuum, the residue is extracted with AcOEt,the organic phase is washed with a buffer solution of pH 2 and withwater and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 12.8 g of the expected product after crystallization fromether.

Preparation 1.5 2-(3,4-Dichlorophenyl)-2-(2-hydroxyethyl)morpholine

A suspension of 1.6 g of lithium aluminum hydride in 25 ml of THF isheated to 60° C., a solution of 4 g of the compound obtained in step Fof Preparation 1.3 in 20 ml of THF is added dropwise and the mixture isstirred for 30 minutes under reflux. After cooling, 1.5 ml of water, 1.5ml of 4 N NaOH and then 4.5 ml of water are added. The mineral salts arefiltered off on Celite®, the filtrate is decanted and the organic phaseis evaporated under vacuum. The residue is taken up with ether and driedover Na₂ SO₄ and the solvent is evaporated off under vacuum to give 3.6g of the expected product.

Preparation 1.6 2-(3,4-Dichlorophenyl)-2-(3-hydroxypropyl)morpholine

A)5-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)pentanenitrile

47 ml of a 1.5 M solution of lithium diisopropylamide in THF are cooledto -60° C., a solution of 19.3 g of the compound obtained in step B ofPreparation 1.3 in 100 ml of THF is added dropwise and the mixture isstirred for 30 minutes at -60° C. 17 g of 3-bromopropyl benzoate arethen added dropwise at -60° C. and the reaction mixture is stirred whilethe temperature is allowed to rise to RT. It is concentrated undervacuum, the residue is extracted with ether, the organic phase is washedwith water and with saturated NaCl solution and dried over Na₂ SO₄ andthe solvent is evaporated off under vacuum to give 21 g of the expectedproduct after crystallization from hexane.

B)5-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)pentylamine

A mixture of 20 g of the compound obtained in the previous step and 7 gof Raney® nickel in 300 ml of MeOH is hydrogenated at RT and atatmospheric pressure. The catalyst is filtered off and the filtrate isconcentrated under vacuum. The residue is taken up with water andextracted with ether, the organic phase is washed with water and driedover Na₂ SO₄ and the solvent is evaporated off under vacuum to give 20 gof the expected product, which is used as such.

C)N-(2-Chloroacetyl)-5-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-(tetrahydropyran-2-yloxy)pentylamine

A solution of 9 g of the compound obtained in the previous step and 2.4g of triethylamine in 100 ml of DCM is cooled to 0° C., a solution of2.23 g of chloroacetyl chloride in 20 ml of DCM is added dropwise andthe reaction mixture is stirred for 30 minutes. It is concentrated undervacuum, the residue is extracted with ether, the organic phase is washedwith water and dried over Na₂ SO₄ and the solvent is evaporated offunder vacuum to give 9.5 g of the expected product, which is used assuch.

D)N-(2-Chloroacetyl)-5-(benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxypentylamine

A saturated solution of gaseous HCl in ether is added to a solution of 9g of the compound obtained in the previous step in 50 ml of DCM and 50ml of MeOH until the pH is 1, and the mixture is stirred for 30 minutesat RT. It is concentrated under vacuum, the residue is extracted withether, the organic phase is washed with water and with saturated NaHCO₃solution and dried over Na₂ SO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica H using a DCM/MeOHmixture (100/3; v/v) as the eluent to give 4.7 g of the expectedproduct, which is used as such.

E) 6-(3,4-Dichlorophenyl)-6-(3-hydroxypropyl)morpholin-3-one

A mixture of 2.95 g of the compound obtained in the previous step, 40 mlof propan-2-ol and 3 ml of 10 N NaOH solution is stirred for 2 hours atRT. The reaction mixture is concentrated under vacuum, the residue isextracted with DCM, the organic phase is washed with water and driedover Na₂ SO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica H using a gradient of a DCM/MeOH mixture(100/2; v/v to 100/5; v/v) as the eluent to give 0.5 g of the expectedproduct. M.p.=130-132° C.

F) 2-(3,4-Dichlorophenyl)-2-(3-hydroxypropyl)morpholine

A suspension of 0.82 g of lithium aluminum hydride in 10 ml of THF isheated to 60° C., a solution of 2 g of the compound obtained in theprevious step in 20 ml of THF is added dropwise and the mixture isstirred for 30 minutes under reflux. After cooling, 1 ml of water, 1 mlof 4 N NaOH and then 3 ml of water are added. The mineral salts arefiltered off on Celite®, the filtrate is decanted and the organic phaseis evaporated under vacuum. The residue is taken up with ether and driedover Na₂ SO₄ and the solvent is evaporated off under vacuum to give 2 gof the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 0.8 to 2.2 ppm: u: 4H 2.5to 3.7 ppm: u: 8H 4.3 ppm: t: 1H 7.2 to 7.7 ppm: u: 3H

Preparation 1.75-[2-(Benzoyloxy)ethyl]-5-(3,4-dichlorophenyl)oxazolidin-2-one

A) 4-(Benzoyloxy)-2-(3,4-dichlorophenyl)-2-hydroxybutylaminehydrochloride

A saturated solution of gaseous HCl in ether is added at RT to asolution of 12 g of the compound obtained in step D of Preparation 1.3in 50 ml of MeOH until the pH is 1, and the reaction mixture is stirredfor 1 hour at RT. It is concentrated under vacuum, the residue is takenup with DCM and the precipitate formed is wrung and washed with ether togive 3.4 g of the expected product after recrystallization frompropan-2-ol. M.p.=200-204° C.

B) 5-[2-(Benzoyloxy)ethyl]-5-(3,4-dichlorophenyl)oxazolidin-2-one

1.4 g of 1,1'-carbonyldiimidazole are added at RT to a solution of 3 gof the compound obtained in the previous step and 0.85 g oftriethylamine in 30 ml of 1,2-dichloroethane and the reaction mixture isstirred for 30 minutes at RT and then heated at 50° C. for 2 hours. Itis concentrated under vacuum, the residue is taken up with water andextracted with DCM, the organic phase is washed with a buffer solutionof pH 2 and with water and dried over Na₂ SO₄ and the solvent isevaporated off under vacuum to give 3 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.6 ppm: mt: 2H 3.75 ppm:AB system: 2H 4.35 ppm: mt 2H 7.4 to 7.8 ppm: u: 8H 7.9 ppm: s: 1H

Preparation 1.86-(3,4-Dichlorophenyl)-1-methyl-6-[2-(tetrahydropyran-2-yloxy)ethyl]piperazine-2,3-dione

A) 2-(3,4-Dichlorophenyl)-2-(methylamino)acetonitrile hydrochloride

A mixture of 10 g of 3,4-dichlorobenzaldehyde and 9.5 ml ofcyanotrimethylsilane is cooled in an ice bath, 10 mg of zinc iodide areadded and the mixture is stirred for 30 minutes at RT. 20 ml of a 33%solution of methylamine in EtOH are then added and the mixture is heatedat 40° C. for 2 hours. The solvent is concentrated under vacuum, theresidue is extracted with ether and the organic phase is dried overMgSO₄ and filtered. A saturated solution of gaseous HCl in ether isadded to the filtrate until the pH is 1, and acetone is then added untilthe product precipitates. The precipitate formed is wrung, washed withether and dried to give 12.8 g of the expected product. M.p.=172° C.

B)2-(tert-Butoxycarbonyl-N-methylamino)-2-(3,4-dichlorophenyl)acetonitrile

Concentrated NaOH solution is added to an aqueous suspension of 12.8 gof the compound obtained in the previous step until the pH is 13, themixture is extracted with ether, the organic phase is dried over MgSO₄and the solvent is evaporated off under vacuum. The residue is taken upwith 20 ml of 1,4-dioxane, 12.5 g of di-tert-butyl dicarbonate are addedand the reaction mixture is heated at 60° C. for 2 hours. It isconcentrated under vacuum, the residue is extracted with ether, theorganic phase is washed with a buffer solution of pH 2, with saturatedNaCl solution and with 10% Na₂ CO₃ solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica using heptane and then a heptane/AcOEt mixture (96/4; v/v) asthe eluent to give 12.7 g of the expected product, which is used assuch.

C)2-(tert-Butoxycarbonyl-N-methylamino)-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butanenitrile

A solution of 11.1 g of the compound obtained in the previous step in 60ml of DMF is added dropwise to a suspension of 1.5 g of sodium hydride(60% dispersion in oil) in 50 ml of DMF, the temperature beingmaintained at 25° C., and the mixture is stirred for 1 hour at RT. Asolution of 8.1 g of 1-bromo-2-(tetrahydropyran-2-yloxy)ethane in 20 mlof DMF is then added and the reaction mixture is heated at 60° C. for 4hours. After cooling to RT, it is poured into a mixture of ice and abuffer of pH 2 and extracted with ether, the organic phase is washedtwice with water and dried over MgSO₄ and the solvent is evaporated offunder vacuum. The residue is chromatographed on silica using heptane andthen a heptane/AcOEt mixture (75/25; v/v) as the eluent to give 13.2 gof the expected product, which is used as such.

D)2-(tert-Butoxycarbonyl-N-methylamino)-2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butylamine

A mixture of 13.2 g of the compound obtained in the previous step and 4g of Raney® nickel in 150 ml of EtOH and 50 ml of 20% aqueous ammoniasolution is hydrogenated at 30° C. and at atmospheric pressure. After 5hours, the catalyst is filtered off and the filtrate is concentratedunder vacuum. The residue is extracted with ether, the organic phase iswashed twice with water and dried over MgSO₄ and the solvent isevaporated off under vacuum to give 12.6 g of the expected product,which is used as such.

E) 2-(3,4-Dichlorophenyl)-4-hydroxy-2-(methylamino)butylaminehydrochloride

A mixture of 4.6 g of the compound obtained in the previous step and 10ml of concentrated HCl solution in 40 ml of MeOH is heated at 70° C. for1 hour. The solvent is then concentrated under vacuum, the residue istaken up with acetone and the precipitate formed is wrung, washed withether and dried to give 2.79 g of the expected product. M.p.=240° C.(dec.).

F)6-(3,4-Dichlorophenyl)-6-(2-hydroxyethyl)-1-methylpiperazine-2,3-dione

Concentrated NaOH solution is added to an aqueous suspension of 5.3 g ofthe compound obtained in the previous step until the pH is 13, themixture is extracted with ether, the organic phase is dried over MgSO₄and the solvent is evaporated off under vacuum. The product obtained (4g) is taken up with 50 ml of EtOH, 2.57 g of diethyl oxalate are addedand the reaction mixture is stirred for 1 hour at RT. It is concentratedunder vacuum and the residue is taken up with 60 ml of toluene andrefluxed for 70 hours. It is concentrated under vacuum to give 2.8 g ofthe expected product after crystallization from DCM. M.p.=260° C.

G)6-(3,4-Dichlorophenyl)-1-methyl-6-[2-(tetrahydropyran-2-yloxy)ethyl]piperazine-2,3-dione

0.1 g of p-toluenesulfonic acid monohydrate and then 1.26 ml of3,4-dihydro-2H-pyran are added to a suspension of 2.8 g of the compoundobtained in the previous step in 50 ml of DCM and the reaction mixtureis stirred overnight at RT. It is washed with 10% Na₂ CO₃ solution andwith water, the organic phase is dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is chromatographed on silicausing AcOEt and then an AcOEt/MeOH mixture (93/7; v/v) as the eluent togive 3.1 g of the expected product, which is used as such.

Preparation 1.92-(3,4-Dichlorophenyl)-1-methyl-2-[2-(tetrahydropyran-2-yloxy)ethyl]piperazine

A solution of 2 g of the compound obtained in Preparation 1.8 in 20 mlof THF is added dropwise to a suspension of 1.2 g of lithium aluminumhydride in 20 ml of THF and the mixture is refluxed for 1 hour. Aftercooling, 5 ml of water are added, the mineral salts are filtered off,the filtrate is concentrated under vacuum, the residue is taken up withether, the organic phase is dried over MgSO₄ and the solvent isevaporated off under vacuum to give 1.9 g of the expected product in theform of an oil.

Preparation 1.106-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one

A) 2-(3,4-Difluorophenyl)-2-hydroxyacetonitrile

A solution of 80.2 g of Na₂ S₂ O₅ in 250 ml of water is heated to 50°C., 50 g of 3,4-difluorobenzaldehyde are added and the reaction mixtureis stirred for 1 hour at 50° C. and left to stand overnight at RT. It iscooled to 0° C., a solution of 77.7 g of KCN in 100 ml of water is addeddropwise, the mixture is stirred while the temperature is allowed torise to RT, and stirring is then continued for 1 hour at RT. Thereaction mixture is extracted with ether, the organic phase is washedwith water and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 48 g of the expected product, which is used as such.

B) 2-(3,4-Difluorophenyl)-2-(tetrahydropyran-2-yloxy)acetonitrile

A solution of 48 g of the compound obtained in the previous step and 0.2g of p-toluenesulfonic acid monohydrate in 500 ml of DCM is cooled to 0°C., a solution of 28.6 g of 3,4-dihydro-2H-pyran in 50 ml of DCM isadded dropwise, the mixture is stirred while the temperature is allowedto rise to RT, and stirring is then continued overnight at RT. Thereaction mixture is concentrated under vacuum, the residue is extractedwith DCM, the organic phase is washed with 10% Na₂ CO₃ solution and withwater and dried over Na₂ SO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using a toluene/AcOEtmixture (100/15; v/v) as the eluent to give 43 g of the expectedproduct, which is used as such.

C)4-(Benzoyloxy)-2-(3,4-difluorophenyl)-2-(tetrahydropyran-2-yloxy)butanenitrile

133 ml of a 1.5 M solution of lithium diisopropylamide in THF are cooledto -60° C., a solution of 43 g of the compound obtained in the previousstep in 250 ml of THF is added dropwise and the mixture is stirred for30 minutes at -60° C. A solution of 45.8 g of 2-bromoethyl benzoate in100 ml of THF is then added dropwise at -60° C. and the reaction mixtureis stirred while the temperature is allowed to rise to RT. It isconcentrated under vacuum, the residue is extracted with ether, theorganic phase is washed with water and with a buffer solution of pH 4and dried over Na₂ SO₄ and the solvent is evaporated off under vacuum.The residue is chromatographed on silica using a toluene/AcOEt mixture(100/5; v/v) as the eluent to give 47 g of the expected product, whichis used as such.

D)4-(Benzoyloxy)-2-(3,4-difluorophenyl)-2-(tetrahydropyran-2-yloxy)butylamine

A mixture of 47 g of the compound obtained in the previous step and 10 gof Raney® nickel in 400 ml of EtOH is hydrogenated at RT and atatmospheric pressure. The catalyst is filtered off and the filtrate isconcentrated under vacuum. The residue is taken up with water andextracted with ether, the organic phase is washed with water and driedover Na₂ SO₄ and the solvent is evaporated off under vacuum to give 45 gof the expected product, which is used as such.

E) 4-(Benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylaminehydrochloride

A saturated solution of gaseous HCl in ether is added at RT to asolution of 45 g of the compound obtained in the previous step in 250 mlof MeOH until the pH is 1, and the reaction mixture is stirred for 30minutes at RT. It is concentrated under vacuum, the residue is taken upwith ether and the precipitate formed is wrung and washed with ether togive 15 g of the expected product after recrystallization frompropan-2-ol. M.p.=202-204° C.

F)N-(2-Chloroacetyl)-4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylamine

A solution of 12.2 g of the compound obtained in the previous step and7.88 g of triethylamine in 100 ml of DCM is cooled to 0° C., a solutionof 3.85 g of chloroacetyl chloride in 100 ml of DCM is added dropwiseand the reaction mixture is stirred for 30 minutes. It is concentratedunder vacuum, the residue is extracted with an ether/AcOEt mixture(50/50; v/v), the organic phase is washed with water, with a buffersolution of pH 4 and with water and dried over Na₂ SO₄ and the solventis evaporated off under vacuum to give 13.5 g of the expected product,which is used as such.

G) 6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one

A mixture of 13.5 g of the compound obtained in the previous step and20.7 g of K₂ CO₃ in 100 ml of toluene is refluxed overnight. Thereaction mixture is concentrated under vacuum, the residue is taken upwith ether and the mixture is filtered. The filtrate is washed withwater, with a buffer solution of pH 2 and with water and dried overMgSO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H using a DCM/Meoh mixture (100/1; v/v) as theeluent to give 4.9 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.35 ppm: mt: 2H 3.65 ppm:AB system: 2H 3.8 to 4.35 ppm: u: 4H 7.1 to 7.8 ppm: u: 8H 8.2 ppm: bs:1H

Preparation 1.11 2-(3,4-Difluorophenyl)-2-(2-hydroxyethyl)morpholine

A suspension of 1.8 g of lithium aluminum hydride in 20 ml of THF isadded dropwise at RT to a solution of 2.8 g of the compound obtained inPreparation 1.10 in 20 ml of THF and the mixture is then refluxed for 5hours. After cooling, 2 ml of water, 2 ml of 4 N NaOH and then 6 ml ofwater are added. The mineral salts are filtered off and the filtrate isconcentrated under vacuum. The residue is dissolved in DCM, acidified topH 1 by the addition of a saturated solution of gaseous HCl in ether,and extracted with water, the aqueous phase is washed with ether,rendered alkaline to pH 8 by the addition of concentrated NaOH solution,and extracted with DCM, the organic phase is washed with water and driedover MgSO₄ and the solvent is evaporated off under vacuum to give 0.77 gof the expected product, which is used as such in EXAMPLE 27, step A.

Preparation 1.125-[2-(Benzoyloxy)ethyl]-5-(3,4-difluorophenyl)oxazolidin-2-one

1 g of 1,1'-carbonyldiimidazole is added at RT to a solution of 2.1 g ofthe compound obtained in step E of Preparation 1.10 and 0.63 g oftriethylamine in 50 ml of 1,2-dichloroethane and the reaction mixture isthen stirred for 1 hour at RT and heated for 2 hours at 50° C. It isconcentrated under vacuum, the residue is extracted with DCM, theorganic phase is washed with water, with a buffer solution of pH 2 andwith water and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 1.5 g of the expected product.

Preparation 1.135-(3,4-Dichlorophenyl)-1-methyl-5-[2-(tetrahydropyran-2-yloxy)ethyl]imidazolidin-2-one

A)2-(3,4-Dichlorophenyl)-2-(methylamino)-4-(tetrahydropyran-2-yloxy)butylamine

A mixture of 3.4 g of the compound obtained in step E of Preparation1.8, 0.05 g of p-toluenesulfonic acid monohydrate and 2.1 ml of3,4-dihydro-2H-pyran in 30 ml of DMF is heated at 60° C. for 45 minutes.The reaction mixture is poured onto ice, rendered alkaline by theaddition of concentrated NaOH and extracted with ether, the organicphase is washed with water and dried over MgSO₄ and the solvent isevaporated off under vacuum to give 4.3 g of the expected product, whichis used as such.

B)5-(3,4-Dichlorophenyl)-1-methyl-5-[2-(tetrahydropyran-2-yloxy)ethyl]imidazolidin-2-one

1.6 g of 1,1'-carbonyldiimidazole are added to a solution of 3.2 g ofthe compound obtained in the previous step in 100 ml of1,2-dichloroethane and the reaction mixture is stirred for 30 minutes atRT. It is then heated at 60° C. for 2 hours and concentrated undervacuum. The residue is extracted with AcOEt, the organic phase is washedwith a buffer solution of pH 2, with saturated NaCl solution and with10% Na₂ CO₃ solution and dried over MgSO₄ and the solvent is evaporatedoff under vacuum. The residue is chromatographed on silica H using DCMand then a DCM/MeOH mixture (98/2; v/v) as the eluent to give 2.4 g ofthe expected product in the form of an oil.

Preparation 1.146-[3-(Benzoyloxy)propyl]-6-(3,4-dichlorophenyl)morpholin-3-one

A mixture of 7.5 g of the compound obtained in step D of Preparation1.6, 9.3 g of K₂ CO₃ and 3.75 g of sodium iodide in 100 ml of methylethyl ketone is refluxed overnight. After cooling, the reaction mixtureis concentrated under vacuum, the residue is taken up with ether, themineral salts are filtered off, the filtrate is washed with a buffersolution of pH 2 and with water, the organic phase is dried over MgSO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H using DCM and then a gradient of a DCM/MeOHmixture (from 99/1; v/v to 98/2; v/v) as the eluent to give 1.3 g of theexpected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 1.1 to 2.3 ppm: u: 4H 3.65ppm: AB system: 2H 3.8 to 4.4 ppm: u: 4H 7.2 to 8.05 ppm: u: 8H 8.2 ppm:s: 1H

Preparation 1.156-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (-)Isomer

A) 4-(Benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylamine, (+) Isomer

A solution of 41 g of L-(+)-tartaric acid in 1200 ml of MeOH is heatedto the reflux temperature, a solution of 81.4 g of the compound obtainedin step E of Preparation 1.10, in the form of the free base, in 200 mlof MeOH is then added all at once and the mixture is left to crystallizefor 48 hours while the temperature is allowed to return to RT. Thecrystals formed are wrung and washed with ether to give 42.5 g of thetartaric acid salt.

[α]_(D) ²⁰ =+36.2° (c=1; DMF)

The resulting salt is recrystallized from 1450 ml of 70° EtOH to give 35g of the tartaric acid salt after the crystals formed have been wrungand washed with ether.

[α]_(D) ²⁰ =+38.9° (c=1; DMF)

The resulting salt is taken up with 2000 ml of AcOEt, 40 ml of 10% Na₂CO₃ solution are added and then, after stirring and decantation, theorganic phase is washed with water and dried over MgSO₄ and the solventis evaporated off under vacuum to give 23.5 g of the expected productafter crystallization from an iso ether/pentane mixture.M.p.=100.5-100.6° C.

[α]_(D) ²⁰ =+42.5° (c=1; MeOH)

B)N-(2-Chloroacetyl)-4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylamine,(+) Isomer

A solution of 23.5 g of the compound obtained in the previous step and8.1 g of triethylamine in 300 ml of DCM is cooled to 0° C., a solutionof 8.3 g of chloroacetyl chloride in 50 ml of DCM is added dropwise andthe reaction mixture is stirred for 30 minutes at 0° C. It isconcentrated under vacuum, the residue is extracted with an AcOEt/ethermixture (50/50; v/v), the organic phase is washed with a buffer solutionof pH 2 and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 24.8 g of the expected product after crystallization froman iso ether/pentane mixture.

[α]_(D) ²⁰ =+26.1° (c=1; MeOH)

C) 6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (-)Isomer

A solution of 23.6 g of the compound obtained in the previous step in750 ml of THF is cooled to 0° C., 13.7 g of potassium tert-butylate areadded and the reaction mixture is stirred for 15 minutes. It isconcentrated under vacuum, the residue is extracted with AcOEt, theorganic phase is washed with a buffer solution of pH 2 and with waterand dried over MgSO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica H using a DCM/MeOH mixture (from100/1; v/v to 100/1.5; v/v) as the eluent to give 14.5 g of the expectedproduct after crystallization from pentane.

[α]_(D) ²⁰ =-7.1° (c=1; MeOH)

Preparation 1.166-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (+)Isomer

A) 4-(Benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylamine, (-) Isomer

The wringing and wash liquors obtained from the crystallization and thenrecrystallization of the tartaric acid salt prepared in step A ofPreparation 1.15 are concentrated under vacuum. The residue is treatedwith 10% Na₂ CO₃ solution and extracted with AcOEt, the organic phase isdried over MgSO₄ and the solvent is evaporated off under vacuum to give49 g of the amino alcohol in the form of a mixture of isomers. The aminoalcohol is dissolved in 120 ml of MeOH and this solution is added all atonce to a refluxing solution of 24.1 g of D-(-)-tartaric acid in 730 mlof MeOH. The mixture is left to crystallize for 48 hours while thetemperature is allowed to return to RT. The crystals formed are wrungand washed with ether to give 40.7 g of the tartaric acid salt.

The resulting salt is recrystallized from 1445 ml of 70° EtOH to give 35g of the tartaric acid salt after the crystals formed have been wrungand washed with ether. The resulting salt is taken up with 2000 ml ofAcOEt, 10% Na₂ CO₃ solution is added and then, after stirring anddecantation, the organic phase is washed with water and dried over MgSO₄and the solvent is evaporated off under vacuum to give 27 g of theexpected product. M.p.=102° C.

[α]_(D) ²⁰ =-40.5° (c=1; MeOH)

B)N-(2-Chloroacetyl)-4-(benzoyloxy)-2-(3,4-difluorophenyl)-2-hydroxybutylamine,(-) Isomer

A solution of 27 g of the compound obtained in the previous step and 13ml of triethylamine in 500 ml of DCM is cooled to -30° C., 5.8 g ofchloroacetyl chloride are added dropwise and the reaction mixture isstirred for 15 minutes. It is then washed with water, with 1 N HClsolution and with 10% Na₂ CO₃ solution, the organic phase is dried overMgSO₄ and the solvent is evaporated off under vacuum to give 28.6 g ofthe expected product after crystallization from an iso ether/pentanemixture. M.p.=63° C.

[α]_(D) ²⁰ =-31.5° (c=1; MeOH)

C) 6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)morpholin-3-one, (+)Isomer

A solution of 28.5 g of the compound obtained in the previous step in250 ml of THF is cooled to -30° C., 18.5 g of potassium tert-butylateare added all at once and the reaction mixture is stirred for 45minutes. It is poured into 1000 ml of a buffer solution of pH 2 andextracted with ether, the organic phase is dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 20.5 g of the expectedproduct after crystallization from an ether/iso ether mixture. M.p.=92°C.

[α]_(D) ²⁰ =+8.2° (c=1; MeOH)

Preparation 1.172-[2-(Benzoyloxy)ethyl]-2-(3,4-difluorophenyl)morpholine, (-) Isomer

A solution of 12 g of the compound obtained in Preparation 1.15 ((-)isomer) in 75 ml of THF is added dropwise at RT to 100 ml of a 1 Msolution of borane in THF and the reaction mixture is stirred for 30minutes at RT. It is then refluxed for 3 hours, 40 ml of a 1 M solutionof borane in THF are added and reflux is continued for 30 minutes. 80 mlof boiling MeOH are added and reflux is continued for 30 minutes. Thereaction mixture is cooled in an ice bath, 30 ml of a saturated solutionof gaseous HCl in ether are added and the reaction mixture is stirredovernight at RT. It is concentrated under vacuum, the residue is takenup with 10% Na₂ CO₃ solution and extracted with ether, the organic phaseis washed with water and with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum to give 11.2 g ofthe expected product in the form of an oil.

Preparation 1.182-[2-(Benzoyloxy)ethyl]-2-(3,4-difluorophenyl)morpholine, (+) Isomer

A mixture of 19.9 g of the compound obtained in Preparation 1.16 ((+)isomer) and 300 ml of a 1 M solution of borane in THF is heated at 60°C. for 2 hours. 60 ml of boiling MeOH are added and reflux is continuedfor 30 minutes. The reaction mixture is cooled to 10° C., 50 ml of asolution of gaseous HCl in ether are added and the reaction mixture isleft to stand overnight at RT. It is concentrated under vacuum, theresidue is taken up with 300 ml of 10% Na₂ CO₃ solution, 300 ml of etherare added and the mixture is stirred for 30 minutes. After decantation,the organic phase is dried over MgSO₄ and the solvent is evaporated offunder vacuum to give 20 g of the expected product in the form of an oil.

Preparation 1.192-[2-(Benzoyloxy)ethyl]-2-(3,4-dichlorophenyl)morpholine

A solution of 6 g of the compound obtained in Preparation 1.4 in 30 mlof THF is added dropwise at RT to 76 ml of a 1 M solution of borane inTHF and the mixture is then refluxed for 4 hours. 30 ml of MeOH areadded dropwise and reflux is continued for 30 minutes. The reactionmixture is cooled to 0° C., 30 ml of a saturated solution of gaseous HClin ether are added and the reaction mixture is stirred overnight at RT.It is concentrated under vacuum, the residue is taken up with 10% Na₂CO₃ solution and extracted with ether, the organic phase is washed with10% Na₂ CO₃ solution and with water and dried over MgSO₄ and the solventis evaporated off under vacuum to give 5 g of the expected product.

Preparation 1.205-[2-(Benzoyloxy)ethyl]-5-(3,4-difluorophenyl)oxazolidin-2-one, (-)isomer

A mixture of 4 g of the compound obtained in step A of Preparation 1.16((-) isomer) and 2.2 g of 1,1'-carbonyldiimidazole in 40 ml of DCM isstirred for 30 minutes at RT and then refluxed for 1 hour. After coolingto RT, the reaction mixture is washed twice with 1 N HCl solution, theorganic phase is dried over MgSO₄ and the solvent is evaporated offunder vacuum to give4.18 g of the expected product after crystallizationfrom iso ether. M.p.=147° C.

[α]_(D) ²⁰ =-62.2° (c=1; DMF)

Preparation 1.212-[2-(Benzoyloxy)ethyl]-2-(3,4-difluorophenyl)morpholine

48 g of the compound obtained in Preparation 1.10 are added in portionsat RT to 700 ml of a 1 M solution of borane in THF and the mixture isthen heated at 60° C. for 2 hours. 150 ml of MeOH are added dropwise andheating is continued for 30 minutes. The reaction mixture is cooled to10° C., 120 ml of a saturated solution of hydrochloric acid in ether areadded and the reaction mixture is left to stand overnight at RT. It isconcentrated under vacuum, the residue is taken up with 600 ml ofsaturated Na₂ CO₃ solution and 500 ml of ether and the mixture isstirred for 1 hour at RT. After decantation, the organic phase is washedwith water and dried over MgSO₄ and the solvent is evaporated off undervacuum. The residue is taken up with 400 ml of propan-2-ol, 15 g offumaric acid are added, the mixture is stirred for 30 minutes and theprecipitate formed is wrung. It is taken up with 400 ml of 10% Na₂ CO₃solution and extracted with ether, the organic phase is dried over MgSO₄and the solvent is evaporated off under vacuum to give 22 g of theexpected product in the form of an oil.

Preparation 1.225-[2-(Benzoyloxy)ethyl]-5-(3,4-dichlorophenyl)oxazolidine

4 g of 37% aqueous formaldehyde solution are added to a solution of 9 gof the compound obtained in step A of Preparation 1.7 (in the form ofthe free base) in 100 ml of THF and the mixture is then refluxed for 30minutes and stirred overnight at RT. It is concentrated under vacuum,the residue is extracted with ether, the organic phase is washed withwater and dried over Na₂ SO₄ and the solvent is evaporated off undervacuum to give 9 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.4 ppm: mt: 2 H; 3.2 ppm:mt: 2H; 3.8 to 5.0 ppm: u: 4H; 7.0 to 8.0 ppm: u: 8H.

Preparation 1.235-[2-(Benzoyloxy)ethyl]-5-(3,4-difluorophenyl)oxazolidin-2-one, (+)isomer

This compound is prepared by the procedure described in Preparation 1.20from the compound obtained in step A of Preparation 1.15 ((+) isomer).

[α]_(D) ²⁰ =+61° (c=1; DMF)

Preparation 2.1 4-Phenyl-4-(pyrrolidin-1-ylcarbonyl)piperidinehemihydrate

A) 1-tert-Butoxycarbonyl-4-carboxy-4-phenylpiperidine

30 ml of water and 32.9 g of K₂ Co₃ are added to a mixture of 30 g of4-carboxy-4-phenylpiperidine p-toluenesulfonate and 300 ml of dioxane,the resulting mixture is then heated to 60° C. and 18.2 g ofdi-tert-butyl dicarbonate are added dropwise. The reaction mixture isthen heated at 60° C. for 2 hours and under reflux for 30 minutes. Aftercooling to RT, it is concentrated under vacuum, the residue is extractedwith DCM, the organic phase is washed with a buffer solution of pH 2,acidified to pH 4 by the addition of 2 N HCl, washed with a buffersolution of pH 2, with water and with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum to give 23.7 gof the expected product.

B) 1-tert-Butoxycarbonyl-4-(pyrrolidin-1-ylcarbonyl)-4-phenylpiperidine

9.29 g of triethylamine and then 3.27 g of pyrrolidine are added to asolution of 14 g of the compound obtained in the previous step in 200 mlof DCM. The mixture is cooled in an ice bath, 22.4 g of BOP are addedand the reaction mixture is stirred while the temperature is allowed torise to RT. It is concentrated under vacuum, the residue is extractedwith DCM, the organic phase is washed with water, three times with 10%NaOH solution, with water and three times with saturated NaCl solutionand dried over MgSO₄ and the solvent is evaporated off under vacuum togive 16.4 g of the expected product.

C) 4-Phenyl-4-(pyrrolidin-1-ylcarbonyl)piperidine hemihydrate

Concentrated HCl solution is added to a solution of 16.4 g of thecompound obtained in the previous step in 200 ml of MeOH until the pH is1, and the reaction mixture is stirred for 5 hours at RT. It isconcentrated under vacuum, the residue is taken up with acetone and thesolvent is evaporated off under vacuum to give a white solid, which isrecrystallized from propan-2-ol. The product obtained is taken up with10% NaOH solution and extracted with DCM, the organic phase is washedwith 10% NaOH solution and with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum to give 7 g of theexpected product after crystallization from ether. M.p.=126° C.

Preparation 2.2 4-(N',N'-Dimethylureido)-4-phenylpiperidinep-toluenesulfonate hemihydrate

A) 4-Acetamido-1-benzyl-4-phenylpiperidine

This compound is prepared by reacting acetonitrile with1-benzyl-4-hydroxy-4-phenylpiperidine by the method described inEP-A-474561.

B) 4-Amino-1-benzyl-4-phenylpiperidine dihydrochloride

A mixture of 30 g of the compound obtained in the previous step and 58ml of concentrated HCl solution in 135 ml of water is refluxed for 48hours. The reaction mixture is concentrated under vacuum, the residue istaken up with an EtOH/toluene mixture and the solvents are evaporatedoff under vacuum. The residue is dissolved in 50 ml of MeOH andcrystallized by the addition of 250 ml of acetone to give 30.5 g of theexpected product after wringing and drying.

C) 1-Benzyl-4-(N',N'-dimethylureido)-4-phenylpiperidine

A solution of 1.9 g of N,N-dimethylcarbamoyl chloride in 10 ml of1,2-dichloroethane is added dropwise at RT to a solution of 6 g of thecompound obtained in the previous step and 7.14 g of triethylamine in 50ml of 1,2-dichloroethane and the mixture is refluxed for 8 hours. A fewmore drops of N,N-dimethylcarbamoyl chloride are added and reflux iscontinued for 3 hours. The reaction mixture is concentrated undervacuum, the residue is extracted with DCM, the organic phase is washedwith water, with 10% NaOH solution, with water and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using a gradient of aDCM/MeOH mixture (from 99/1; v/v to 96/4; v/v) as the eluent to give 1.8g of the expected product.

D) 4-(N',N'-Dimethylureido)-4-phenylpiperidine p-toluenesulfonatehemihydrate

A mixture of 1.8 g of the compound obtained in the previous step, 1.11 gof p-toluenesulfonic acid monohydrate and 0.2 g of 10%palladium-on-charcoal in 150 ml of 95° EtOH is hydrogenated at 40° C.and at atmospheric pressure. The catalyst is filtered off on Celite® andthe filtrate is evaporated under vacuum. The residue is taken up withacetone and the solvent is evaporated off under vacuum. The productobtained is dissolved in 25 ml of acetone, this solution is added slowlyto 200 ml of ether and the crystalline product formed is wrung to give1.86 g of the expected product. M.p.=120-122° C.

Preparation 2.3 4-(Acetyl-N-methylamino)-4-phenylpiperidinep-toluenesulfonate

A) 1-Benzyl-4-(formylamino)-4-phenylpiperidine

110 ml of acetic anhydride are added dropwise to a solution of 48.9 g ofthe compound obtained in step B of Preparation 2.2 and 25 g of sodiumformate in 340 ml of formic acid and the reaction mixture is stirredovernight at RT. It is concentrated under vacuum, the residue is takenup with water, rendered alkaline by the addition of concentrated NaOHsolution and extracted with DCM, the organic phase is dried over MgSO₄and the solvent is evaporated off under vacuum to give 38.8 g of theexpected product after crystallization from an iso ether/pentanemixture. M.p.=140° C.

B) 1-Benzyl-4-(methylamino)-4-phenylpiperidine

A solution of 38.8 g of the compound obtained in the previous step in400 ml of THF is added slowly to a suspension of 12.5 g of lithiumaluminum hydride in 100 ml of THF and the mixture is refluxed for 3hours. After cooling, a solution of 5 ml of concentrated NaOH in 45 mlof water is added to the reaction mixture, the mineral salts arefiltered off and the filtrate is concentrated under vacuum to give 38 gof the expected product.

C) 4-(Acetyl-N-methylamino)-1-benzyl-4-phenylpiperidine

A solution of 30 g of the compound obtained in the previous step and16.5 ml of triethylamine in 300 ml of DCM is cooled to 0-5° C., 8 ml ofacetyl chloride are added dropwise and the reaction mixture is stirredfor 30 minutes at RT. It is washed twice with water and with 2 N NaOHsolution, the organic phase is dried over MgSO₄ and the solvent isevaporated off under vacuum to give 31.6 g of the expected product aftercrystallization from an iso ether/pentane mixture. M.p.=104° C.

D) 4-(Acetyl-N-methylamino)-4-phenylpiperidine p-toluenesulfonate

A mixture of 5 g of the compound obtained in the previous step, 2.9 g ofp-toluenesulfonic acid monohydrate, 0.5 g of 10% palladium-on-charcoaland 80 ml of EtOH is hydrogenated for 3 hours at 25° C. and atatmospheric pressure. The catalyst is filtered off and the filtrate isconcentrated under vacuum to give 5.7 g of the expected product aftercrystallization from acetone. M.p.=165° C.

Preparation 2.4 4-(Ethoxycarbonylamino)-4-phenylpiperidinetrifluoroacetate

A) 1-tert-Butoxycarbonyl-4-isocyanato-4-phenylpiperidine

A solution of 25 g of the compound obtained in step A of Preparation 2.1and 10.35 g of triethylamine in 100 ml of acetone is cooled to 0-5° C.,a solution of 8.7 g of methyl chloroformate in 30 ml of acetone is addeddropwise at a temperature below 5° C. and the mixture is stirred for 30minutes at 5° C. A solution of 10.66 g of sodium azide in 30 ml of wateris then added dropwise at a temperature below 5° C. and the reactionmixture is stirred for 30 minutes at 5° C. It is poured into 500 ml oficed water and extracted four times with toluene and the organic phaseis washed twice with a buffer solution of pH 2 and with saturated NaClsolution, dried over MgSO₄ and filtered. The filtrate is heated at 90°C. for 1 hour and the solvent is evaporated off under vacuum to give18.9 g of the expected product in the form of an oil.

B) 1-tert-Butoxycarbonyl-4-(ethoxycarbonylamino)-4-phenylpiperidine

A solution of 6.28 g of the compound obtained in the previous step in100 ml of EtOH is refluxed for 5 hours 30 minutes. Two drops oftriethylamine are added and the mixture is then stirred overnight at RTand concentrated under vacuum to give 7.25 g of the expected product.

C) 4-(Ethoxycarbonylamino)-4-phenylpiperidine trifluoroacetate

A solution of 7.25 g of the compound obtained in the previous step in 20ml of TFA is stirred for 30 minutes at RT and then concentrated undervacuum. The residue is taken up with acetone and the solvent isevaporated off under vacuum to give 6.02 g of the expected product aftercrystallization from an acetone/ ether mixture. M.p.=173° C.

Preparation 2.5 4-Benzylquinuclidine

A) 1,4-Dibenzyl-4-cyanopiperidine

A solution of 15 g of 4-cyanopiperidine in 250 ml of THF is cooled to-50° C., 190 ml of a 1.5 M solution of lithium diisopropylamide incyclohexane are added dropwise and the mixture is stirred for 30 minutesat -50° C. 34 ml of benzyl bromide are then added and the mixture isstirred for 3 hours after the temperature has been allowed to rise toRT. The reaction mixture is poured into an ice/concentrated HCl mixture,ether is added and the precipitate formed is wrung and washed withwater. The precipitate is taken up with water, rendered alkaline to pH12 by the addition of concentrated NaOH solution and extracted withether, the organic phase is dried over MgSO₄ and the solvent isevaporated off to give 31.7 g of the expected product aftercrystallization from pentane. M.p.=92° C.

B) 4-Acetyl-1,4-dibenzylpiperidine hydrochloride

55 ml of a 1.6 M solution of methyllithium in ether are added to asolution of 20 g of the compound obtained in the previous step in 400 mlof ether and the reaction mixture is stirred for 3 hours at RT. It ispoured into iced water, the organic phase is decanted and then driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis taken up with 400 ml of water and 40 ml of concentrated HCl andrefluxed for 2 hours. After one night at RT, the crystals formed arewrung, washed with acetone and then with ether and dried to give 17.6 gof the expected product. M.p.=246° C.

C) 1,4-Dibenzyl-4-(2-bromoacetyl)piperidine hydrobromide

1.6 ml of bromine are added to a solution of 10 g of the compoundobtained in the previous step in 40 ml of acetic acid and the reactionmixture is stirred overnight at RT. 50 ml of ether are added and thecrystals formed are wrung and washed with an acetone/ether mixture andthen with ether to give 12.5 g of the expected product. M.p.=205° C.

D) 1,4-Dibenzyl-3-oxoquinuclidinium bromide

Concentrated NaOH solution is added to an aqueous suspension of 12.5 gof the compound obtained in the previous step until the pH is 12, themixture is extracted with ether, the organic phase is dried over MgSO₄and the solvent is evaporated off under vacuum. The residue is taken upwith acetone and stirred for 2 hours at RT. The precipitate is wrung,washed with ether and dried to give 10.08 g of the expected product.M.p.=234° C.

E) 4-Benzyl-3-oxoquinuclidine

A mixture of 10 g of the compound obtained in the previous step and 1 gof 10% palladium-on-charcoal in 200 ml of MeOH is hydrogenated at RT andat atmospheric pressure. The catalyst is filtered off and the filtrateis evaporated under vacuum. The residue is taken up with ether and theprecipitate formed is wrung. The precipitate is dissolved in water andrendered alkaline to pH 12 by the addition of concentrated NaOH solutionand the precipitate formed is wrung, washed with water and dried to give5 g of the expected product. M.p.=111° C.

F) 4-Benzylquinuclidine

A mixture of 5 g of the compound obtained in the previous step, 2.5 g ofhydrazine hydrate and 4.3 g of KOH in 25 ml of ethylene glycol is heatedat 175° C. for 2 hours. The reaction mixture is poured into iced waterand extracted twice with ether, the organic phase is washed with waterand dried over MgSO₄ and the solvent is evaporated off under vacuum. Theresidue is dissolved in acetone and acidified to pH 1 by the addition ofa saturated solution of hydrochloric acid in ether and the precipitateformed is wrung and washed with an acetone/ether mixture (50/50; v/v)and then with ether. The precipitate is dissolved in water, renderedalkaline to pH 12 by the addition of concentrated NaOH solution andextracted with ether, the extract is dried over MgSO₄ and the solvent isevaporated off under vacuum to give 1.8 g of the expected product.M.p.=48° C.

Preparation 2.6 4-Phenyl-4-(pyrrolidin-1-ylcarbonylamino)-piperidinebenzenesulfonate

A) 1-(Benzyloxycarbonyl)-4-carboxy-4-phenylpiperidine

A mixture of 37.7 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate,53.3 g of 30% aqueous NaOH solution and 250 ml of water is cooled to 5°C. A solution of 18 g of benzyl chloroformate in 60 g of acetone isadded rapidly at 5° C. and the reaction mixture is stirred overnightwhile the temperature is allowed to rise to RT. It is washed twice withether and, after decantation, the aqueous phase is acidified to pH 1 bythe addition of concentrated HCl and then 2 N HCl. The precipitateformed is wrung, dried, taken up with ether and wrung again to give 30.6g of the expected product. M.p.=142-144° C.

B)1-(Benzyloxycarbonyl)-4-phenyl-4-(pyrrolidin-1-yl-carbonylamino)piperidine

A mixture of 33.9 g of the compound obtained in the previous step and47.6 g of thionyl chloride in 200 ml of 1,2-dichloroethane is refluxedfor 1 hour. The reaction mixture is concentrated under vacuum, theresidue is taken up with acetone and the solvent is evaporated off undervacuum. The residue is dissolved in 200 ml of acetone and cooled to 5°C., a solution of 13 g of sodium azide in 50 ml of water is addeddropwise and the mixture is stirred for 1 hour. 100 ml of acetone areevaporated off under vacuum at RT, saturated NaHCO₃ solution is added tothe remaining solution, the mixture is extracted with toluene, theorganic phase is washed with water and with saturated NaCl solution anddried over Na₂ SO₄ and 50% by volume of the solvent is evaporated off.The remaining toluene solution is refluxed for 30 minutes and thenconcentrated under vacuum. The residue is taken up with 200 ml of ether,a solution of 7.1 g of pyrrolidine in 20 ml of ether is added dropwiseand the mixture is stirred for 5 minutes. It is concentrated undervacuum, the residue is extracted with DCM, the organic phase is washedwith 2 N HCl solution, with 5% NaHCO₃ solution and with saturated NaClsolution and dried over Na₂ SO₄ and the solvent is evaporated off undervacuum. The residue is dissolved in 40 ml of hot AcOEt, 200 ml of etherare added and the crystalline product formed is wrung to give 31.4 g ofthe expected product.

C) 4-Phenyl-4-(pyrrolidin-1-ylcarbonylamino)piperidine benzenesulfonate

A mixture of 29 g of the compound obtained in the previous step, 11.27 gof benzenesulfonic acid, 2 g of 10% palladium-on-charcoal and 250 ml ofEtOH is hydrogenated at 40° C. and at atmospheric pressure. The catalystis filtered off on Celite® and the filtrate is concentrated undervacuum. The residue is crystallized from an EtOH/acetone mixture to give29.4 g of the expected product. M.p.=185° C.

Preparation 2.7 4-[2-(Dimethylamino)thiazol-4-yl]-4-phenylpiperidinep-toluenesulfonate

A) 1,1-Dimethylthiourea

A solution of 10.67 g of potassium thiocyanate in 100 ml of acetone iscooled in an ice bath, a solution of 12.06 g of pivaloyl chloride in 30ml of acetone is added dropwise and the reaction mixture is stirred for30 minutes while the temperature is allowed to rise to RT. It is cooledto -10° C., 17.9 ml of a 5.6 N solution of dimethylamine in MeOH areadded dropwise and the mixture is stirred while the temperature isallowed to rise to RT. It is concentrated under vacuum, the residue isextracted with ether, the organic phase is washed twice with water andwith saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. The product obtained is taken up with 50 mlof concentrated HCl solution and refluxed for 1 hour. After cooling toRT, the reaction mixture is washed twice with ether, the aqueous phaseis rendered alkaline to pH 9 by the addition of 30% NaOH solution andextracted with DCM, the organic phase is washed with 5% NaOH solutionand with saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is taken up with ether and theprecipitate formed is wrung to give 6.7 g of the expected product.

B) 4-(2-Bromoacetyl)-4-phenylpiperidine hydrobromide

7.9 g of bromine are added rapidly at RT to a suspension of 14 g of4-acetyl-4-phenylpiperidine hydrobromide in 200 ml of DCM and thereaction mixture is stirred overnight at RT. It is diluted by theaddition of 200 ml of ether and the precipitate formed is wrung andwashed with ether to give 16.7 g of the expected product after dryingunder vacuum.

C) 4-[2-(Dimethylamino)thiazol-4-yl]-4-phenylpiperidinep-toluenesulfonate

A mixture of 7.26 g of the compound obtained in step B) and 2.08 g ofthe compound obtained in step A) in 150 ml of EtOH is refluxed for 1hour 30 minutes. After cooling to RT, the mixture is concentrated undervacuum, the residue is taken up with water, rendered alkaline to pH 10by the addition of 10% NaOH solution and extracted with DCM, the organicphase is washed with 10% NaOH solution and with saturated NaCl solutionand dried over MgSO₄ and the solvent is evaporated off under vacuum. Theproduct obtained is dissolved in acetone, a solution of 3.31 g ofp-toluenesulfonic acid monohydrate in 10 ml of acetone is added dropwiseand the crystalline product formed is wrung to give 6.1 g of theexpected product. M.p.=164° C.

Preparation 2.8 4-(Morpholin-4-ylcarbonylamino)-4-phenylpiperidinep-toluenesulfonate monohydrate

A)1-tert-Butoxycarbonyl-4-(morpholin-4-ylcarbonylamino)-4-phenylpiperidine

A solution of 1.74 g of morpholine in 10 ml of acetone is added dropwiseat RT to a solution of 6 g of the compound obtained in step A ofPreparation 2.4 in 100 ml of acetone. The reaction mixture isconcentrated under vacuum, the residue is extracted with AcOEt, theorganic phase is washed with a buffer solution of pH 2 and withsaturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum to give 7.1 g of the expected product.

B) 4-(Morpholin-4-ylcarbonylamino)-4-phenylpiperidine p-toluenesulfonatemonohydrate

15 ml of concentrated HCl solution are added to a solution of 7.1 g ofthe compound obtained in the previous step in 100 ml of MeOH and thereaction mixture is stirred overnight at RT. It is concentrated undervacuum, the residue is taken up with water, rendered alkaline to pH 10by the addition of concentrated NaOH solution and extracted three timeswith DCM, the combined organic phases are washed with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum. The product obtained is dissolved in acetone, a solution of 3.46g of p-toluenesulfonic acid monohydrate in 10 ml of acetone is addeddropwise and the mixture is concentrated under vacuum. The residue istaken up with ether and the precipitate formed is wrung to give 7 g ofthe expected product. M.p.=93° C.

Preparation 2.9 4-Phenyl-4-(pyrrolidin-1-ylaminocarbonyl)piperidinebenzenesulfonate

A)1-(Benzyloxycarbonyl)-4-phenyl-4-(pyrrolidin-1-ylaminocarbonyl)piperidinebenzenesulfonate

A mixture of 11.54 g of the compound obtained in step A of Preparation2.6 and 100 ml of 1,2-dichloroethane is heated to the refluxtemperature, 16.18 g of thionyl chloride are then added and the reactionmixture is refluxed for 1 hour and stirred overnight at RT. It isconcentrated under vacuum, the residue is dissolved in 100 ml of DCM andcooled to 5° C. and 10.3 g of triethylamine and then 5 g of1-aminopyrrolidine hydrochloride are added successively. After stirringfor 1 hour, the reaction mixture is concentrated under vacuum, theresidue is extracted with AcOEt, the organic phase is washed with waterand with saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. The product obtained is dissolved inacetone, ether is added until precipitation occurs, and the precipitateformed is wrung. The precipitate is dissolved in EtOH, 2.61 g ofbenzenesulfonic acid are added and the precipitate formed is wrung togive 9.34 g of the expected product.

B) 4-Phenyl-4-(pyrrolidin-1-ylaminocarbonyl)piperidine benzenesulfonate

A mixture of 9.34 g of the compound obtained in the previous step, 1 gof 5% palladium-on-charcoal and 200 ml of EtOH is hydrogenated for 3hours at 40° C. and at atmospheric pressure. The catalyst is filteredoff and the filtrate is concentrated under vacuum to give 6.13 g of theexpected product after crystallization from an EtOH/acetone mixture.

Preparation 2.10 4-Benzyl-4-(pyrrolidin-1-ylcarbonylamino)piperidinep-toluenesulfonate

A) 4-Cyanopiperidine

25 g of isonipecotamide (or piperidine-4-carboxamide) are added in smallportions to 70 ml of POCl₃ and the reaction mixture is refluxed for 4hours. It is concentrated under vacuum, the residue is taken up withice, rendered alkaline to pH 13 by the addition of concentrated NaOHsolution and extracted with DCM and then 4 times with ether, thecombined organic phases are dried over MgSO₄ and the solvents areevaporated off under vacuum. The oil obtained is distilled under reducedpressure to give 6.4 g of the expected product. B.p.=108-110° C. under2400 Pa.

B) 4-Cyano-1,4-dibenzylpiperidine

A solution of 15 g of the compound obtained in the previous step in 250ml of THF is cooled to -50° C., 190 ml of a 1.5 M solution of lithiumdiisopropylamide in cyclohexane are added dropwise and the mixture isstirred for 30 minutes at -50° C. 34 ml of benzyl bromide are then addedand the reaction mixture is stirred while the temperature is allowed torise to RT. After 3 hours at RT, it is poured into a mixture of ice andconcentrated HCl, ether is added and the precipitate formed is wrung andwashed with water. The precipitate is taken up with water, renderedalkaline to pH 13 by the addition of concentrated NaOH solution andextracted with ether, the organic phase is dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 31.7 g of the expectedproduct after crystallization from pentane. M.p.=92° C.

C) 1,4-Dibenzyl-4-carboxypiperidine

6 g of the compound obtained in the previous step are added to asolution of 25 ml of water, 25 ml of concentrated H₂ SO₄ and 25 ml ofAcOH and the reaction mixture is heated at 140° C. for 5 hours. Aftercooling, it is poured onto ice, the pH is brought to 6.5 by the additionof concentrated NaOH solution and the mixture is stirred untilcrystallization occurs. The crystalline product is wrung and washed withwater. The product is taken up with MeOH, wrung and washed with ether togive 3 g of the expected product. M.p.=262° C.

D) 1,4-Dibenzyl-4-isocyanatopiperidine

A mixture of 2 g of the compound obtained in the previous step and 1.6 gof phosphorus pentachloride in 40 ml of chloroform is heated at 60° C.for 1 hour. The reaction mixture is concentrated under vacuum, theresidue is taken up with 40 ml of acetone, a solution of 2 g of sodiumazide in 5 ml of water is added and the mixture is stirred for 30minutes at RT. It is concentrated under vacuum at RT, the residue istaken up with ether, the organic phase is washed with saturated Na₂ CO₃solution and with water and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is taken up with 40 ml oftoluene and refluxed for 1 hour. It is concentrated under vacuum to give2 g of the expected product in the form of an oil.

E) 1,4-Dibenzyl-4-(pyrrolidin-1-ylcarbonylamino)piperidine

1.5 ml of pyrrolidine are added at RT to a solution of 5 g of thecompound obtained in the previous step in 50 ml of DCM and the reactionmixture is stirred for 2 hours at RT. It is concentrated under vacuum,the residue is taken up with pentane and the precipitate formed is wrungand washed with pentane to give 4.5 g of the expected product afterdrying. M.p.=126° C.

F) 4-Benzyl-4-(pyrrolidin-1-ylcarbonyamino)piperidine p-toluenesulfonate

A mixture of 4.2 g of the compound obtained in the previous step, 2.1 gof p-toluenesulfonic acid monohydrate, 0.4 g of 10%palladium-on-charcoal and 50 ml of EtOH is hydrogenated for 48 hours atRT and at atmospheric pressure. The catalyst is filtered off on Celite®and the filtrate is concentrated under vacuum. The residue is taken upwith ether and the precipitate formed is wrung to give 4.99 g of theexpected product. M.p.>180° C.

Preparation 2.11 4-(Methoxycarbonylamino)-4-phenylpiperidinep-toluenesulfonate hemihydrate

A solution of 6.05 g of the compound obtained in step A of Preparation2.4 in 100 ml of MeOH is refluxed for 5 hours. 1 drop of triethylamineis added and the mixture is stirred overnight at RT. Concentrated HClsolution is then added until the pH is 1, and the reaction mixture isconcentrated under vacuum. The residue is taken up with 10% NaOHsolution and extracted with DCM, the organic phase is washed with 10%NaOH solution and with saturated NaCl solution and dried over MgSO₄ andthe solvent is evaporated off under vacuum. The product obtained isdissolved in acetone, a solution of 3.57 g of p-toluenesulfonic acidmonohydrate in 10 ml of acetone is added dropwise and the mixture isconcentrated under vacuum. The product obtained is taken up with etherand the solvent is evaporated off under vacuum to give 7.17 g of theexpected product. M.p.=159° C.

Preparation 2.12 4-(2-Amino-1,3,4-oxadiazol-5-yl)-4-phenylpiperidinep-toluenesulfonate hemihydrate

A) 1-(Benzyloxycarbonyl)-4-(chloroformyl)-4-phenylpiperidine

A mixture of 17.1 g of the compound obtained in step A of Preparation2.6 and 24 g of thionyl chloride in 150 ml of 1,2-dichloroethane isrefluxed for 1 hour. It is concentrated under vacuum, the residue istaken up with chloroform and the solvent is evaporated off under vacuum.The residue is taken up with an ether/pentane mixture and the solventsare evaporated off under vacuum again to give 20 g of the expectedproduct in the form of a gum, which is used as such.

B) 1-(Benzyloxycarbonyl)-4-carbazoyl-4-phenylpiperidine

A solution of 16 g of hydrazine monohydrate in 40 ml of EtOH is cooledto -50° C., a solution of 11.44 g of the compound obtained in theprevious step in 20 ml of 1,2-dimethoxyethane is added dropwise and themixture is stirred while the temperature is allowed to rise to RT. It isconcentrated under vacuum, the residue is taken up with water andextracted with DCM, the organic phase is washed with water and withsaturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is taken up with anEtOH/benzene mixture and the solvents are evaporated off under vacuum togive 11.2 g of the expected product in the form of a gum, which is usedas such.

C)4-(2-Amino-1,3,4-oxadiazol-5-yl)-1-(benzyloxycarbonyl)-4-phenylpiperidine

A solution of 3.39 g of cyanogen bromide in 10 ml of EtOH is added at RTto a solution of 11.2 g of the compound obtained in the previous step in60 g of EtOH and the reaction mixture is refluxed for 1 hour. It isconcentrated to 50 ml of EtOH and water is then added dropwise until thevolume of the reaction mixture is 400 ml. The crystalline product formedis wrung and washed with water and then with DCM, with AcOEt and withether to give 8 g of the expected product.

D) 4-(2-Amino-1,3,4-oxadiazol-5-yl)-4-phenylpiperidinep-toluenesulfonate hemihydrate

A mixture of 7.85 g of the compound obtained in the previous step, 3.95g of p-toluenesulfonic acid monohydrate, 0.8 g of 10%palladium-on-charcoal, 350 ml of 95° EtOH and 10 ml of water ishydrogenated at 50° C. and at atmospheric pressure. After 3 hours, thecatalyst is filtered off on Celite® and the filtrate is concentratedunder vacuum. The residue is taken up with acetone and the crystallineproduct formed is wrung and washed with acetone and then with ether togive 7.65 g of the expected product. M.p.=183-185° C.

Preparation 2.13 4-[(Acetyl-N-methylamino)methyl]-4-phenylpiperidinep-toluenesulfonate

A) 4-(Aminomethyl)-1-benzyl-4-phenylpiperidine

A suspension of 2.8 g of lithium aluminum hydride in 50 ml of THF iscooled to 0° C. and a solution of 20 g of1-benzyl-4-cyano-4-phenylpiperidine in 50 ml of THF is added dropwise.The reaction mixture is stirred for 1 hour at RT and then heated for 1hour at 40° C. It is cooled in an ice bath and 3 ml of water, 3 ml of 4N NaOH solution and 12 ml of water are added successively. The mineralsalts are filtered off and the filtrate is evaporated under vacuum. Theresidue is chromatographed on silica H using a gradient of a DCM/MeOHmixture (from 100/3; v/v to 100/10; v/v) as the eluent to give 11 g ofthe expected product.

B) 1-Benzyl-4-[(N-formylamino)methyl]-4-phenylpiperidine

25 ml of acetic anhydride are added dropwise at RT to a mixture of 11 gof the compound obtained in the previous step in 76 ml of formic acidand the reaction mixture is then stirred for 5 hours. It is concentratedunder vacuum, the residue is taken up with water, rendered alkaline topH 14 by the addition of concentrated NaOH and extracted with ether, theextract is washed with water and dried over Na₂ SO₄ and the solvent isevaporated off under vacuum to give 12 g of the expected product.

C) 1-Benzyl-4-[(N-methylamino)methyl]-4-phenylpiperidine

A suspension of 3.9 g of lithium aluminum hydride in 50 ml of THF isheated to 40° C., a solution of 12 g of the compound obtained in theprevious step in 50 ml of THF is added dropwise and the mixture is thenrefluxed for 3 hours. After cooling in an ice bath, 4 ml of water, 4 mlof 4 N NaOH solution and 12 ml of water are added successively. Themineral salts are filtered off and the filtrate is concentrated undervacuum. The residue is extracted with ether, the extract is dried overNa₂ SO₄ and the solvent is evaporated off under vacuum to give 10 g ofthe expected product.

D) 4-[(Acetyl-N-methylamino)methyl]-1-benzyl-4-phenylpiperidine

0.863 g of acetyl chloride is added to a solution of 3.3 g of thecompound obtained in the previous step and 1.4 g of triethylamine in 50ml of DCM and the reaction mixture is stirred for 2 hours at RT. It isconcentrated under vacuum, the residue is taken up with water andextracted with ether, the extract is washed with water and dried overNa₂ SO₄ and the solvent is evaporated off. The residue ischromatographed on silica H using a DCM/MeOH mixture (100/3; v/v) as theeluent to give 2.4 g of the expected product.

E) 4-[(Acetyl-N-methylamino)methyl]-4-phenylpiperidinep-toluenesulfonate

A mixture of 2.3 g of the compound obtained in the previous step, 1.2 gof p-toluenesulfonic acid monohydrate, 0.23 g of 10%palladium-on-charcoal and 100 ml of MeOH is hydrogenated at RT and atatmospheric pressure. The catalyst is filtered off and the filtrate isevaporated under vacuum to give 2.7 g of the expected product aftertrituration in ether and wringing.

Preparation 2.144-[(Ethoxycarbonyl-N-methylamino)methyl]-4-phenylpiperidinep-toluenesulfonate

A) 1-Benzyl-4-[(ethoxycarbonyl-N-methylamino)methyl]-4-phenylpiperidine

A solution of 0.85 g of ethyl chloroformate in 10 ml of DCM is addeddropwise at RT to a solution of 2.3 g of the compound obtained in step Cof Preparation 2.13 and 1.03 g of triethylamine in 50 ml of DCM and thereaction mixture is stirred for 30 minutes at RT. It is concentratedunder vacuum, the residue is taken up with water and extracted withether, the organic phase is washed with water and with saturated NaClsolution and dried over Na₂ SO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica H using a DCM/MeOHmixture (100/3; v/v) as the eluent to give 2.3 g of the expectedproduct.

B) 4-[(Ethoxycarbonyl-N-methylamino)methyl]-4-phenylpiperidinep-toluenesulfonate

A mixture of 2.3 g of the compound obtained in the previous step, 1.19 gof p-toluenesulfonic acid monohydrate, 0.7 g of 5% palladium-on-charcoaland 50 ml of DCM is hydrogenated at 40° C. and at atmospheric pressure.The catalyst is filtered off on Celite® and the filtrate is concentratedunder vacuum to give 2.7 g of the expected product.

Preparation 2.154-[(N',N'-Dimethyl-N-methylureido)methyl]-4-phenylpiperidinep-toluenesulfonate

A) 1-Benzyl-4-[(N',N'-dimethyl-N-methylureido)methyl]-4-phenylpiperidine

A solution of 0.92 g of N,N-dimethylcarbamoyl chloride in 20 ml of DCMis added dropwise at RT to a solution of 2.5 g of the compound obtainedin step C of Preparation 2.13 and 1.11 g of triethylamine in 50 ml ofDCM and the reaction mixture is then refluxed for 3 hours. It isconcentrated under vacuum, the residue is taken up with water andextracted with ether, the organic phase is washed with water and withsaturated NaCl solution and dried over Na₂ SO₄ and the solvent isevaporated off under vacuum. The residue is chromatographed on silica Husing a DCM/MeOH mixture (100/3; v/v) as the eluent to give 2.92 g ofthe expected product.

B) 4-[(N',N'-Dimethyl-N-methylureido)methyl]-4-phenylpiperidinep-toluenesulfonate

A mixture of 2.92 g of the compound obtained in the previous step, 1.52g of p-toluenesulfonic acid monohydrate, 0.3 g of 10%palladium-on-charcoal and 50 ml of MeOH is hydrogenated at 40° C. and atatmospheric pressure. The catalyst is filtered off on Celite® and thefiltrate is concentrated under vacuum to give 2.6 g of the expectedproduct after trituration of the residue in a pentane/iso ether mixture,followed by wringing.

Preparation 2.16 4-Carbamoyl-4-(piperid-1-yl)piperidine dihydrochloride

A) 1-Benzyl-4-cyano-4-(piperid-1-yl)piperidine

A solution of 5.3 g of sodium cyanide in 20 ml of water is addeddropwise at RT to a solution of 18.9 g of 1-benzylpiperid-4-one and12.16 g of piperidine hydrochloride in 25 ml of MeOH and 25 ml of waterand the mixture is stirred for 48 hours at RT. The precipitate formed iswrung, washed with water and dried under vacuum to give 27 g of theexpected product.

B) 1-Benzyl-4-carbamoyl-4-(piperid-1-yl)piperidine 10 g of the compoundobtained in the previous step are added to 50 ml of 95% sulfuric acidand the reaction mixture is heated at 100° C. for 45 minutes. Aftercooling to RT, it is poured onto 100 g of ice, 250 ml of DCM are added,with cooling, the organic phase is decanted and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The solid product obtained isrecrystallized from 300 ml of an acetonitrile/toluene mixture (65/35;v/v) to give 9.7 g of the expected product. M.p.=150-160° C.

C) 4-Carbamoyl-4-(piperid-1-yl)piperidine dihydrochloride

10 g of ammonium formate and 2.5 g of 5% palladium-on-charcoal are addedto a solution of 9.7 g of the compound obtained in the previous step in200 ml of MeOH and the mixture is stirred for 2 hours at RT. It isfiltered on Celite® and the filtrate is evaporated under vacuum. Theresidue is dissolved in 2 N HCl solution, rendered alkaline to pH 13 bythe addition of 40% NaOH solution and extracted with chloroform, theorganic phase is dried over MgSO₄ and the solvent is evaporated offunder vacuum. The product obtained is dissolved in an MeOH/DCM mixture,acidified to pH 1 by the addition of a saturated solution ofhydrochloric acid in ether and evaporated under vacuum to give 5 g ofthe expected product. M.p.=185° C.

Preparation 2.17 4-Phenyl-4-ureidopiperidine benzenesulfonate

A) 1-(Benzyloxycarbonyl)-4-isocyanato-4-phenylpiperidine

A mixture of 50.89 g of the compound obtained in step A) of Preparation2.6 and 71.4 g of thionyl chloride in 400 ml of 1,2-dichloroethane isrefluxed for 1 hour. The reaction mixture is concentrated under vacuum,the residue is taken up with acetone and the solvent is evaporated offunder vacuum. The residue is dissolved in 200 ml of acetone and cooledto 5° C., a solution of 19.5 g of sodium azide in 50 ml of water isadded dropwise and the mixture is stirred for 2 hours at RT. The acetoneis evaporated off under vacuum at RT, saturated NaHCO₃ solution is addedto the remaining solution, the mixture is extracted with toluene, theorganic phase is washed with water and with saturated NaCl solution anddried over Na₂ SO₄ and 50% by volume of the solvent is evaporated off.The remaining toluene solution is refluxed for 1 hour and thenconcentrated under vacuum to give 54 g of the expected product in theform of an orange oil, which crystallizes.

B) 1-(Benzyloxycarbonyl)-4-phenyl-4-ureidopiperidine

Excess ammonia gas is bubbled at RT into a solution of 29 g of thecompound obtained in the previous step in 300 ml of ether and 300 ml ofDCM and the reaction mixture is then stirred overnight at RT. It isconcentrated under vacuum, the residue is taken up with hot acetone andthe temperature is allowed to drop to RT. As soon as the productcrystallizes, an ether/AcOEt mixture is added and the crystals formedare then wrung to give 26.4 g of the expected product.

C) 4-Phenyl-4-ureidopiperidine benzenesulfonate

A mixture of 25 g of the compound obtained in the previous step, 11.2 gof benzenesulfonic acid, 3 g of 5% palladium-on-charcoal and 300 ml ofEtOH is hydrogenated at 40° C. and at atmospheric pressure. The reactionmixture is diluted by the addition of water and MeOH, the catalyst isfiltered off on Celite® and the filtrate is concentrated under vacuum togive 26.45 g of the expected product after crystallization from acetone.M.p.=235° C.

Preparation 2.18 4-(N'-Methylureido)-4-phenylpiperidine benzenesulfonate

A) 1-(Benzyloxycarbonyl)-4-(N'-methylureido)-4-phenylpiperidine

A solution of 25 g of the compound obtained in step A of Preparation2.17 in 300 ml of ether is cooled to 5° C. and excess gaseousmethylamine is bubbled in. The reaction mixture is diluted by theaddition of 150 ml of DCM and stirred overnight at RT. It isconcentrated under vacuum, the residue is taken up with hot AcOEt andthe temperature is allowed to return to RT. Ether is added untilprecipitation occurs, and the precipitate formed is wrung to give 24 gof the expected product.

B) 4-(N'-Methylureido)-4-phenylpiperidine benzenesulfonate

A mixture of 23 g of the compound obtained in the previous step, 9.9 gof benzenesulfonic acid, 3 g of 5% palladium-on-charcoal and 300 ml of95° EtOH is hydrogenated at 40° C. and at atmospheric pressure. Thecatalyst is filtered off on Celite® and the filtrate is concentratedunder vacuum. The residue is taken up with acetone and the precipitateformed is wrung to give 22.36 g of the expected product. M.p.=227° C.

Preparation 2.19 4-(3,3-Dimethylcarbazoyl)-4-phenylpiperidinep-toluenesulfonate

A) 1-(Benzyloxycarbonyl)-4-(3,3-dimethylcarbazoyl)-4-phenylpiperidinep-toluenesulfonate

A solution of 7.15 g of the compound obtained in step A of Preparation2.12 in 60 g of DCM is cooled to 5° C., a solution of 1.44 g of1,1-dimethylhydrazine and 4.04 g of triethylamine in 20 ml of DCM isadded dropwise and the reaction mixture is stirred overnight at RT. Itis concentrated under vacuum, the residue is taken up with water andextracted with AcOEt, the organic phase is washed with saturated NaClsolution and dried over Na₂ SO₄ and the solvent is evaporated off undervacuum. The product obtained is dissolved in 100 ml of acetone, asolution of 3.59 g of p-toluenesulfonic acid monohydrate in 10 ml ofacetone is added rapidly and the mixture is concentrated under vacuum.The residue is taken up with an ether/DCM mixture and the precipitateformed is wrung to give 9.65 g of the expected product.

B) 4-(3,3-Dimethylcarbazoyl)-4-phenylpiperidine p-toluenesulfonate

A mixture of 9.5 g of the compound obtained in the previous step and 0.9g of 10% in palladium-on-charcoal in 100 ml of 95° EtOH is hydrogenatedat 30° C. and at atmospheric pressure. The catalyst is filtered off onCelite® and the filtrate is concentrated under vacuum. The residue istaken up with 100 ml of acetone and the crystalline product formed iswrung and washed with ether to give 7 g of the expected product.M.p.=210-212° C.

Preparation 2.20 4-[(Ethylaminocarbonyloxy)methyl]-4-phenylpiperidinehydrochloride

A) 4-Methoxycarbonyl-4-phenylpiperidine p-toluenesulfonate

1 g of p-toluenesulfonic acid monohydrate is added to a solution of 10 gof 4-carboxy-4-phenylpiperidine p-toluenesulfonate in 300 ml of MeOH andthe reaction mixture is refluxed for 3 days. It is concentrated undervacuum, the residue is taken up with acetone, and ether is added untilprecipitation occurs. 9.34 g of the expected product are obtained afterwringing of the precipitate formed.

B) 4-Hydroxymethyl-4-phenylpiperidine

A suspension of 1.16 g of lithium aluminum hydride in 50 ml of THF iscooled to -20° C., 4 g of the compound obtained in the previous step areadded and the mixture is stirred overnight while the temperature isallowed to rise to RT. It is hydrolyzed by the addition of 1.2 ml ofwater and then 2.5 ml of 10% NaOH solution and 2.5 ml of water. Themixture is diluted with ether, the mineral salts are filtered off andthe filtrate is evaporated under vacuum to give 1.8 g of the expectedproduct.

C) 1-tert-Butoxycarbonyl-4-(hydroxymethyl)-4-phenylpiperidine

26.05 g of di-tert-butyl dicarbonate are added to a solution of 22.8 gof the compound obtained in the previous step in 250 ml of1,2-dimethoxyethane and the reaction mixture is refluxed for 2 hours. Itis concentrated under vacuum, the residue is taken up with DCM, theorganic phase is washed with a buffer solution of pH 2 and withsaturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum to give 17.86 g of the expected productafter crystallization from ether. M.p.=134° C.

D)1-tert-Butoxycarbonyl-4-[(ethylaminocarbonyloxy)methyl]-4-phenylpiperidine

A mixture of 2.91 g of the compound obtained in the previous step, 2.4 gof ethyl isocyanate and 2 drops of triethylamine in 30 ml of toluene isstirred overnight at RT. The reaction mixture is then heated at 100° C.for 24 hours and concentrated under vacuum. The residue is taken up withether, the organic phase is washed with a buffer solution of pH 2 andwith saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum to give 3.85 g of the expected product inthe form of an oil.

E) 4-[(Ethylaminocarbonyloxy)methyl]-4-phenylpiperidine hydrochloride

10 ml of concentrated HCl are added to a solution of 3.85 g of thecompound obtained in the previous step in 50 ml of MeOH and the mixtureis heated at 60° C. for 2 hours. It is concentrated under vacuum, theresidue is taken up with acetone and the solvent is evaporated off undervacuum to give 2.6 g of the expected product after crystallization froman AcOEt/ether mixture. M.p.=240-242° C.

Preparation 2.21 4-(Acetoxymethyl)-4-phenylpiperidine

0.785 g of acetyl chloride is added at RT to a solution of 2.91 g of thecompound obtained in step C of Preparation 2.20 and 1.31 g oftriethylamine in 50 ml of DCM and the mixture is stirred for 30 minutesat RT. It is concentrated under vacuum, the residue is taken up withwater and extracted with AcOEt, the organic phase is washed twice withwater and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The oily residue is taken upwith 20 ml of trifluoroacetic acid and the mixture is stirred for 10minutes at RT. It is concentrated under vacuum, the residue is taken upwith water, the aqueous phase is rendered alkaline to pH 11 by theaddition of concentrated NaOH solution and extracted with DCM, theorganic phase is washed 5 times with water and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 1.6 g of the expected product.

Preparation 2.224-Benzyl-4-[(ethoxycarbonyl-N-methylamino)methyl]piperidinebenzenesulfonate

A) 1-Benzyl-4-carbamoylpiperidine

85.5 g of benzyl bromide are added dropwise at RT to a mixture of 58.2 gof isonipecotamide and 69 g of K₂ CO₃ in 275 ml of DMF and the reactionmixture is stirred for 2 hours at 50° C. It is concentrated undervacuum, the residue is taken up with water and extracted with DCM, theorganic phase is washed with water and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum to give 62 g of the expectedproduct after crystallization from 300 ml of water and drying undervacuum.

B) 1-Benzyl-4-cyanopiperidine

A mixture of 62 g of the compound obtained in the previous step and 200ml of POCl₃ is refluxed for 2 hours. It is concentrated under vacuum,the residue is taken up with water, rendered alkaline to pH 13 by theaddition of concentrated NaOH solution and extracted with DCM, theorganic phase is washed with water and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum. The oil obtained is distilledunder reduced pressure to give 52 g of the expected product. B.p.=120°C. under 10 Pa.

C) 1,4-Dibenzyl-4-cyanopiperidine

200 ml of a 1.5 M solution of lithium diisopropylamide in cyclohexane,diluted in 100 ml of THF, are cooled to -50° C., a solution of 52 g ofthe compound obtained in the previous step in 100 ml of THF is addeddropwise and the mixture is stirred for 30 minutes at -50° C. A solutionof 51.3 g of benzyl bromide in 100 ml of THF is then added dropwise at atemperature between -30° C. and -25° C. and the mixture is stirred whilethe temperature is allowed to rise to RT. It is concentrated undervacuum, the residue is taken up with water and extracted with ether, theorganic phase is washed with water and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum to give 64 g of the expectedproduct after crystallization from pentane.

D) 4-(Aminomethyl)-1,4-dibenzylpiperidine

A solution of 14.5 g of the compound obtained in the previous step in 50ml of THF is added dropwise at RT to a suspension of 1.95 g of lithiumaluminum hydride in 50 ml of THF and the mixture is then refluxed for 6hours. After cooling to RT, 2 ml of water, 2 ml of 4 N NaOH solution and6 ml of water are added. The mineral salts are filtered off on Celite®,the filtrate is decanted, the organic phase is dried over Na₂ SO₄ andthe solvent is evaporated off under vacuum to give 14.7 g of theexpected product.

E) 1,4-Dibenzyl-4-[(formylamino)methyl]piperidine

42 ml of acetic anhydride are added dropwise at RT to a solution of 14.7g of the compound obtained in the previous step in 126 ml of formic acidand the mixture is stirred for 3 hours at RT. It is concentrated undervacuum, the residue is taken up with water, rendered alkaline to pH 13by the addition of concentrated NaOH solution and extracted with AcOEt,the organic phase is washed with water and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum to give 14.5 g of the expectedproduct.

F) 1,4-Dibenzyl-4-[(methylamino)methyl]piperidine

A solution of 14.5 g of the compound obtained in the previous step in100 ml of THF is added dropwise at 40° C. to a suspension of 5 g oflithium aluminum hydride in 100 ml of THF and the mixture is thenrefluxed for 4 hours. After cooling to RT, 5 ml of water, 5 ml of 4 NNaOH solution and 15 ml of water are added. The mineral salts arefiltered off on Celite®, the filtrate is decanted, the organic phase isdried over Na₂ SO₄ and the solvent is evaporated off under vacuum togive 12.8 g of the expected product.

G) 1,4-Dibenzyl-4-[(ethoxycarbonyl-N-methylamino)methyl]piperidine

1.26 g of ethyl chloroformate are added dropwise at RT to a solution of3 g of the compound obtained in the previous step and 1.18 g oftriethylamine in 50 ml of 1,2-dichloroethane and the mixture is stirredfor 1 hour at RT. It is concentrated under vacuum, the residue is takenup with water and extracted with ether, the organic phase is dried overNa₂ SO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H using a DCM/MeOH mixture (100/3; v/v) as theeluent to give 1.6 g of the expected product.

H) 4-Benzyl-4-[(ethoxycarbonyl-N-methylamino)methyl]-piperidinebenzenesulfonate

A mixture of 1.6 g of the compound obtained in the previous step, 0.66 gof benzenesulfonic acid, 0.2 g of 10% palladium-on-charcoal and 30 ml ofMeOH is hydrogenated at 27° C. and at atmospheric pressure. The catalystis filtered off on Celite® and the filtrate is concentrated under vacuumto give 1.44 g of the expected product.

Preparation 2.234-Benzyl-4-[(methanesulfonyl-N-methylamino)methyl]piperidinebenzenesulfonate

A) 1,4-Dibenzyl-4-[(methanesulfonyl-N-methylamino)methyl]piperidine

1.26 g of methanesulfonyl chloride are added dropwise at RT to asolution of 3.2 g of the compound obtained in step F of Preparation 2.22and 1.26 g of triethylamine in 50 ml of 1,2-dichloroethane and themixture is stirred for 1 hour at RT. It is concentrated under vacuum,the residue is taken up with water and extracted with AcOEt, the organicphase is dried over Na₂ SO₄ and the solvent is evaporated off undervacuum to give 3.8 g of the expected product.

B) 4-Benzyl-4-[(methanesulfonyl-N-methylamino)methyl]piperidinebenzenesulfonate

A mixture of 3.8 g of the compound obtained in the previous step, 1.58 gof benzenesulfonic acid, 0.8 g of 10% palladium-on-charcoal and 30 ml ofMeOH is hydrogenated at RT and at atmospheric pressure. The catalyst isfiltered off on Celite® and the filtrate is concentrated under vacuum togive 4.6 g of the expected product after crystallization from aDCM/ether mixture.

Preparation 2.244-Benzyl-4-[(N',N'-dimethyl-N-methylureido)methyl]piperidinehydrochloride

A) 1,4-Dibenzyl-4-[(N',N'-dimethyl-N-methylureido)methyl]piperidine

1.12 g of N,N-dimethylcarbamoyl chloride are added dropwise at RT to asolution of 3.2 g of the compound obtained in step F of Preparation 2.22and 1.2 g of triethylamine in 40 ml of 1,2-dichloroethane and themixture is refluxed for 4 hours. It is concentrated under vacuum, theresidue is taken up with water and extracted with ether, the organicphase is dried over Na₂ SO₄ and the solvent is evaporated off undervacuum to give 3.6 g of the expected product.

B) 4-Benzyl-4-[(N',N'-dimethyl-N-methylureido)methyl]piperidinehydrochloride

A mixture of 3.6 g of the compound obtained in the previous step, 3.1 gof ammonium formate and 0.8 g of 5% palladium-on-charcoal in 50 ml ofMeOH is stirred for 1 hour 30 minutes. The catalyst is filtered off andthe solvent is evaporated off under vacuum. The residue is dissolved inDCM, a saturated solution of hydrochloric acid in ether is added untilthe pH is 1, and the solvents are evaporated off under vacuum to give3.2 g of the expected product.

Preparation 2.25 4-Carbamoyl-4-(morpholin-4-yl)piperidine

A) 1-Benzyl-4-cyano-4-(morpholin-4-yl)piperidine

2.5 ml of morpholine and then 5.1 g of Na₂ S₂ O₅ are added to a mixtureof 5 g of 1-benzylpiperid-4-one and 1.9 g of potassium cyanide in 50 mlof an EtOH/water mixture (50/50; v/v) and the mixture is heated at 60°C. for 2 hours. A further 2.5 ml of morpholine are added and thereaction mixture is stirred overnight at RT. Water is added and thecrystalline product formed is wrung to give 5.5 g of of the expectedproduct.

B) 1-Benzyl-4-carbamoyl-4-(morpholin-4-yl)piperidine

A mixture of 14 g of the compound obtained in the previous step and 50ml of 95% sulfuric acid is heated at 100° C. for 2 hours. After coolingto RT, the reaction mixture is poured onto 100 g of ice, brought to pH 7by the addition of concentrated NH₄ OH solution and extracted with DCM,the organic phase is washed with water and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H using a DCM/MeOH mixture (100/5; v/v to 100/10; v/v) as theeluent to give 3.4 g of the expected product after crystallization fromiso ether.

C) 4-Carbamoyl-4-(morpholin-4-yl)piperidine

3.1 g of ammonium formate and 0.8 g of 5% palladium-on-charcoal areadded to a solution of 3.4 g of the compound obtained in the previousstep in 50 ml of MeOH and the mixture is stirred for 2 hours at RT. Thecatalyst is filtered off on Celite® and the filtrate is evaporated undervacuum to give 2.2 g of the expected product after crystallization frompropan-2-ol.

EXAMPLE 13-Benzyl-5-[2-(4-benzylpiperid-1-yl)ethyl]-5-(3,4-dichlorophenyl)tetrahydro-2H-1,3-oxazin-2-onehydrochloride monohydrate

A)3-Benzyl-5-(3,4-dichlorophenyl)-5-[2-(tetrahydropyran-2-yloxy)ethyl]tetrahydro-2H-1,3-oxazin-2-one

A solution of 4 g of the compound obtained in Preparation 1.1 in 60 g ofTHF is cooled to +5° C., 1.37 g of potassium tert-butylate are added anda solution of 1.92 g of benzyl bromide in 15 ml of THF is then addeddropwise. The reaction mixture is stirred while the temperature isallowed to rise to RT, and concentrated under vacuum. The residue isextracted with AcOEt, the organic phase is washed three times with waterand twice with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 4.2 g of the expectedproduct, which is used as such.

B)3-Benzyl-5-(3,4-dichlorophenyl)-5-(2-hydroxyethyl)tetrahydro-2H-1,3-oxazin-2-one0.25 hydrate

A saturated solution of gaseous HCl in ether is added to a solution of4.2 g of the compound obtained in the previous step in 40 ml of MeOHuntil the pH is 1, and the reaction mixture is stirred for 48 hours atRT. It is concentrated under vacuum, the residue is taken up with asaturated solution of gaseous HCl in MeOH and the solvent is evaporatedoff under vacuum. The residue is taken up with ether and the precipitateformed is wrung to give 3.44 g of the expected product. M.p.=143° C.

C)3-Benzyl-5-(3,4-dichlorophenyl)-5-[2-(methanesulfonyloxy)ethyl]tetrahydro-2H-1,3-oxazin-2-one

A solution of 1.4 g of the compound obtained in the previous step and0.45 g of triethylamine in 50 ml of DCM is cooled to +5° C. and asolution of 0.46 g of methanesulfonyl chloride in 5 ml of DCM is addeddropwise. After the addition, the reaction mixture is concentrated undervacuum, the residue is taken up with water and extracted with AcOEt, theorganic phase is washed twice with water and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 1.7 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.03 ppm: t: 2H 2.98 ppm:s: 3H 3.78 ppm: AB system: 2H 3.83 ppm: t: 2H 4.1 to 4.8 ppm: u: 4H 7.0to 7.6 ppm: u: 8H

D)3-Benzyl-5-[2-(4-benzylpiperid-1-yl)ethyl]-5-(3,4-dichlorophenyl)tetrahydro-2H-1,3-oxazin-2-onehydrochloride monohydrate

A mixture of 1.6 g of 4-benzylpiperidine, 1.7 g of the compound obtainedin the previous step and 0.6 g of potassium iodide in 10 ml of DMF isheated at 60° C. for 2 hours 30 minutes. After cooling to RT, thereaction mixture is poured into water and extracted with AcOEt, theorganic phase is washed twice with water and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica H using DCM as theeluent. The product obtained is taken up with a saturated solution ofgaseous HCl in ether and the precipitate formed is wrung to give 0.9 gof the expected product. M.p.=122° C.

EXAMPLE 23-Benzyl-5-(3,4-dichlorophenyl)-5-[2-(4-hydroxy-4-phenylpiperid-1-yl)ethyl]tetrahydro-2H-1,3-oxazin-2-onehydrochloride

This compound is prepared by the procedure described in step D ofEXAMPLE 1 from 1.32 g of 4-hydroxy-4-phenylpiperidine, 1.55 g of thecompound obtained in step C of EXAMPLE 1 and 0.56 g of potassium iodidein 10 ml of DMF. The residue is chromatographed on silica H using DCMand then a DCM/MeOH mixture (96/4; v/v) as the eluent. The productobtained is dissolved in DCM and acidified to pH 1 by the addition of asaturated solution of gaseous HCl in ether and the solvents areevaporated off under vacuum to give 0.72 g of the expected compoundafter crystallization from ether. M.p.=172° C.

EXAMPLE 35-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-3-benzyl-5-(3,4-dichlorophenyl)tetrahydro-2H-1,3-oxazin-2-onehydrochloride 1.5 hydrate

This compound is prepared by the procedure described in step D ofEXAMPLE 1 from 2.77 g of 4-acetamido-4-phenylpiperidine, 1.7 g of thecompound obtained in step C of EXAMPLE 1 and 0.61 g of potassium iodidein 10 ml of DMF. The residue is chromatographed on silica H using DCMand then a DCM/MeOH mixture (97/3; v/v) as the eluent. The residue istaken up with a saturated solution of gaseous HCl in ether and thesolvent is evaporated off under vacuum to give 0.6 g of the expectedproduct after crystallization from AcOEt. M.p.=168° C.

EXAMPLE 43-[3,5-Bis(trifluoromethyl)benzyl]-5-(3,4-dichlorophenyl)-5-[2-(4-phenylpiperid-1-yl)ethyl]tetrahydro-2H-1,3-oxazin-2-onehydrochloride hemihydrate

A)3-[3,5-Bis(trifluoromethyl)benzyl]-5-(3,4-dichlorophenyl)-5-[2-(tetrahydropyran-2-yloxy)ethyl]tetrahydro-2H-1,3-oxazin-2-one

A solution of 3.7 g of the compound obtained in Preparation 1.1 in 60 gof THF is cooled to +5° C., 1.27 g of potassium tert-butylate are addedand a solution of 2.72 g of 3,5-bis(trifluoromethyl)benzyl chloride in15 ml of THF is then added dropwise. The reaction mixture is stirredwhile the temperature is allowed to rise to RT, and concentrated undervacuum. The residue is taken up with water and extracted with AcOEt, theorganic phase is washed with water and with saturated NaCl solution anddried over MgSO₄ and the solvent is evaporated off under vacuum to give5.9 g of the expected product, which is used as such.

B)3-[3,5-Bis(trifluoromethyl)benzyl]-5-(3,4-dichlorophenyl)-5-(2-hydroxyethyl)tetrahydro-2H-1,3-oxazin-2-one

A saturated solution of gaseous HCl in ether is added to a solution of5.9 g of the compound obtained in the previous step in 50 ml of MeOHuntil the pH is 1, and the reaction mixture is stirred for 15 minutes atRT. It is concentrated under vacuum, the residue is taken up twice witha saturated solution of gaseous HCl in MeOH and the solvent isevaporated off under vacuum. The residue is taken up with hexane and theprecipitate formed is wrung to give 3.9 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 1.9 ppm: t: 2H 2.9 to 3.6ppm: u: 4H 3.8 ppm: AB system: 2H 4.35 ppm: s: 2H 5.45 ppm: bs: 1H 7.1to 7.8 ppm: u: 3H 8.0 to 8.5 ppm: u: 3H 8.9 ppm: bs: 1H

C)3-[3,5-Bis(trifluoromethyl)benzyl]-5-(3,4-dichlorophenyl)-5-[2-(methanesulfonyloxy)ethyl]tetrahydro-2H-1,3-oxazin-2-one

A solution of 3 g of the compound obtained in the previous step and 0.7g of triethylamine in 50 ml of DCM is cooled to +5° C., a solution of0.66 g of methanesulfonyl chloride in 6 ml of DCM is added dropwise andthe reaction mixture is stirred while the temperature is allowed to riseto RT. It is concentrated under vacuum, the residue is taken up withwater and extracted with AcOEt, the organic phase is washed with water,with 2 N HCl solution, with water, with 5% NaHCO₃ solution, with waterand with saturated NaCl solution and dried over MgSO₄ and the solvent isevaporated off under vacuum to give 3.4 g of the expected product.

D)3-[3,5-Bis(trifluoromethyl)benzyl]-5-(3,4-dichlorophenyl)-5-[2-(4-phenylpiperid-1-yl)ethyl]tetrahydro-2H-1,3-oxazin-2-onehydrochloride hemihydrate

A mixture of 0.32 g of 4-phenylpiperidine, 1 g of the compound obtainedin the previous step and 0.28 g of potassium iodide in 5 ml of DMF isheated at 60° C. for 3 hours. After cooling, the reaction mixture ispoured into water and extracted with AcOEt, the organic phase is washedwith water and with saturated NaCl solution and dried over MGSO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H using DCM and then a DCM/MeOH mixture (98/2; v/v) as theeluent. The product obtained is taken up with a saturated solution ofgaseous HCl in ether and the precipitate formed is wrung to give 0.22 gof the expected product. M.p.=174° C.

EXAMPLE 55-[2-(4-Benzylpiperid-1-yl)ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]-5-(3,4-dichlorophenyl)tetrahydro-2H-1,3-oxazin-2-onehydrochloride 1.5 hydrate

This compound is prepared by the procedure described in step D ofEXAMPLE 4 from 0.3 g of 4-benzylpiperidine, 0.8 g of the compoundobtained in step C of EXAMPLE 4, 0.24 g of potassium iodide and 5 ml ofDMF. The residue is chromatographed on silica H using DCM and then aDCM/MeOH mixture (96/4; v/v) as the eluent. The product obtained istaken up with a saturated solution of gaseous HCl in ether and theprecipitate formed is wrung to give 0.13 g of the expected product.M.p.=124° C.

EXAMPLE 65-[2-(4-Anilinopiperid-1-yl)ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]-5-(3,4-dichlorophenyl)tetrahydro-2H-1,3-oxazin-2-onedihydrochloride monohydrate

A mixture of 0.3 g of 4-anilinopiperidine, 0.8 g of the compoundobtained in step C of EXAMPLE 4 and 0.69 g of potassium carbonate in 5ml of acetonitrile is heated at 50-60° C. for 5 hours. The reactionmixture is poured into water and extracted with AcOEt, the organic phaseis washed twice with water and with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica H using DCM and then a DCM/MeOH mixture(96/4; v/v) as the eluent. The product obtained is taken up with asaturated solution of gaseous HCl in ether and the precipitate formed iswrung to give 0.12 g of the expected product. M.p.=158° C.

EXAMPLE 75-(3,4-Dichlorophenyl)-5-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]tetrahydro-2H-1,3-oxazin-2-onechloride 2.5 hydrate

A mixture of 0.53 g of 4-phenyl-1-azabicyclo[2.2.2]octane and 1.4 g ofthe compound obtained in step C of EXAMPLE 4 in 5 ml of DMF is heated at60° C. for 5 hours. After cooling to RT, the reaction mixture is pouredinto water and extracted with DCM, the organic phase is washed twicewith 2 N HCl solution and three times with saturated NaCl solution anddried over MgSO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using DCM and then a DCM/MeOHmixture (92/8; v/v) as the eluent. The product obtained is taken up withether and the precipitate formed is wrung to give 0.21 g of the expectedproduct. M.p.=138° C.

EXAMPLE 83-Benzyl-5-[3-(4-benzylpiperid-1-yl)propyl]-5-(3,4-dichlorophenyl)tetrahydro-2H-1,3-oxazin-2-onehydrochloride

A)3-Benzyl-5-(3,4-dichlorophenyl)-5-[3-(tetrahydropyran-2-yloxy)propyl]tetrahydro-2H-1,3-oxazin-2-one

A solution of 12.5 g of the compound obtained in Preparation 1.2 in 150ml of THF is cooled to +5° C., 4.13 g of potassium tert-butylate areadded and a solution of 5.78 g of benzyl bromide in 30 ml of THF is thenadded dropwise. The mixture is stirred for 1 hour at RT and concentratedunder vacuum. The residue is taken up with water and extracted withAcOEt, the organic phase is washed twice with water and with saturatedNaCl solution and dried over MgSO₄ and the solvent is evaporated offunder vacuum to give the expected product, which is used as such.

B)3-Benzyl-5-(3,4-dichlorophenyl)-5-(3-hydroxypropyl)tetrahydro-2H-1,3-oxazin-2-one

The compound obtained in the previous step is taken up with a saturatedsolution of gaseous HCl in MeOH and the reaction mixture is stirred for2 hours at RT. It is concentrated under vacuum, the residue is taken uptwice with a saturated solution of gaseous HCl in MeOH and the solventis evaporated off under vacuum. The residue is chromatographed on silicausing DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent to give10.6 g of the expected product, which is used as such.

C)3-Benzyl-5-(3,4-dichlorophenyl)-5-[3-(methanesulfonyloxy)propyl]tetrahydro-2H-1,3-oxazin-2-one

A solution of 10 g of the compound obtained in the previous step and3.07 g of triethylamine in 350 ml of DCM is cooled to +5° C. and asolution of 3.19 g of methanesulfonyl chloride in 35 ml of DCM is addeddropwise. After the addition, the reaction mixture is concentrated undervacuum, the residue is taken up with water and extracted with AcOEt, theorganic phase is washed twice with water and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 11 g of the expected product, which is used as such.

D)3-Benzyl-5-[3-(4-benzylpiperid-1-yl)propyl]-5-(3,4-dichlorophenyl)tetrahydro-2H-1,3-oxazin-2-onehydrochloride

A mixture of 1.86 g of 4-benzylpiperidine, 2 g of the compound obtainedin the previous step and 0.7 g of potassium iodide in 10 ml of DMF isheated at 50° C. for 2 hours. After cooling to RT, the reaction mixtureis poured into water and extracted with AcOEt, the organic phase iswashed twice with water and with saturated NaCl solution and dried overMgSO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H using DCM and then a DCM/MeOH mixture (98/2;v/v) as the eluent. The product obtained is taken up with a saturatedsolution of gaseous HCl in ether and the solvent is evaporated off undervacuum to give 1.4 g of the expected product after crystallization fromAcOEt. M.p.=219° C.

EXAMPLE 93-Benzyl-5-(3,4-dichlorophenyl)-5-[3-(4-hydroxy-4-phenylpiperid-1-yl)propyl]tetrahydro-2H-1,3-oxazin-2-onehydrochloride hemihydrate

This compound is prepared by the procedure described in step D ofEXAMPLE 8 from 1.6 g of 4-hydroxy-4-phenylpiperidine, 2 g of thecompound obtained in step C of EXAMPLE 8 and 0.75 g of potassium iodidein 10 ml of DMF. The residue is chromatographed on silica H using DCMand then a DCM/MeOH mixture (96/4; v/v) as the eluent. The productobtained is taken up with a saturated solution of gaseous HCl in etherand the precipitate formed is wrung to give 1.34 g of the expectedproduct. M.p.=125° C.

EXAMPLE 105-[3-(4-Acetamido-4-phenylpiperid-1-yl)propyl]-3-benzyl-5-(3,4-dichlorophenyl)tetrahydro-2H-1,3-oxazin-2-onehydrochloride 1.5 hydrate

2.02 g of 4-acetamido-4-phenylpiperidine hydrochloride are dissolved in5 ml of water, rendered alkaline to pH 13 by the addition ofconcentrated NaOH and extracted with DCM, the organic phase is driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis taken up with 10 ml of DMF, 1.5 g of the compound obtained in step Cof EXAMPLE 8 and 0.53 g of potassium iodide are added and the reactionmixture is heated at 50° C. for 2 hours 30 minutes. It is poured intowater and extracted with AcOEt, the organic phase is washed three timeswith water and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica using DCM and then a DCM/MeOH mixture (96/4; v/v) as theeluent. The product obtained is taken up with a saturated solution ofgaseous HCl in ether and the solvent is evaporated off under vacuum togive 1.34 g of the expected product after crystallization from AcOEt.M.p.=145° C.

EXAMPLE 113-Benzyl-5-(3,4-dichlorophenyl)-5-[3-[4-(N-phenylacetamido)piperid-1-yl]propyl]tetrahydro-2H-1,3-oxazin-2-onehydrochloride

A mixture of 1.76 g of 4-anilinopiperidine, 2 g of the compound obtainedin step C of EXAMPLE 8 and 0.75 g of potassium iodide in 10 ml of DMF isheated at 50° C. for 1 hour 30 minutes. The reaction mixture is pouredinto water and extracted with AcOEt, the organic phase is washed threetimes with water and with saturated NaCl solution and dried over MgSO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4;v/v) as the eluent. The product obtained is taken up with 10 ml ofacetic anhydride and the reaction mixture is stirred for 48 hours at RT.It is concentrated under vacuum, the residue is extracted with AcOEt,the organic phase is washed twice with 20% aqueous ammonia solution,twice with water and with saturated NaCl solution and dried over MgSO₄and the solvent is evaporated off under vacuum. The product obtained istaken up with a saturated solution of gaseous HCl in ether and thesolvent is evaporated off under vacuum to give 1.4 g of the expectedproduct after crystallization from AcOEt. M.p.=195° C.

EXAMPLE 123-Benzyl-5-(3,4-dichlorophenyl)-5-[3-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]propyl]tetrahydro-2H-1,3-oxazin-2-onechloride hemihydrate

A mixture of 1.2 g of 4-phenyl-1-azabicyclo[2.2.2]octane and 2 g of thecompound obtained in step C of EXAMPLE 8 in 10 ml of DMF is heated at50° C. for 3 hours. After cooling to RT, the reaction mixture is pouredinto water and extracted with DCM, the organic phase is washed withwater, with saturated NaCl solution, twice with 2 N HCl solution, twicewith water and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is taken up withAcOEt and the precipitate formed is wrung to give 1.56 g of the expectedproduct. M.p.=235° C.

EXAMPLE 133-Benzyl-5-(3,4-dichlorophenyl)-5-[3-(4-benzylpyridinio-1)propyl]tetrahydro-2H-1,3-oxazin-2-onechloride dihydrate

A mixture of 1.07 g of 4-benzylpyridine and 2 g of the compound obtainedin step C of EXAMPLE 8 in 10 ml of DMF is heated at 90° C. for 6 hours.After cooling to RT, the reaction mixture is poured into water andextracted with DCM, the organic phase is washed with water and threetimes with saturated NaCl solution and dried over MgSO₄ and the solventis evaporated off under vacuum. The residue is chromatographed on silicausing DCM and then a DCM/MeOH mixture (90/10; v/v) as the eluent. Theproduct obtained is dissolved in the minimum amount of acetone, ether isadded until precipitation occurs, and the precipitate formed is wrung togive 0.8 g of the expected product. M.p.=84° C.

EXAMPLE 144-Benzyl-6-(3,4-dichlorophenyl)-6-[2-(4-hydroxy-4-phenylpiperid-1-yl)ethyl]morpholin-3-onehydrochloride hemihydrate

A) 4-Benzyl-6-(3,4-dichlorophenyl)-6-(2-hydroxyethyl)morpholin-3-one

0.51 g of potassium tert-butylate is added at RT to a solution of 1.7 gof the compound obtained in Preparation 1.3 in 30 ml of THF, 0.77 g ofbenzyl bromide is then added slowly and the reaction mixture is heatedfor 2 hours at 50° C. It is concentrated under vacuum, the residue istaken up with water and extracted with ether, the organic phase iswashed with water and dried over Na₂ SO₄ and the solvent is evaporatedoff under vacuum. The residue is chromatographed on silica H using aDCM/MeOH mixture (100/0.5; v/v) as the eluent. The product obtained (1g) is dissolved in 10 ml of MeOH and acidified to pH 1 by the additionof a saturated solution of gaseous HCl in ether and the solvents areevaporated off under vacuum. The residue is extracted with ether, theorganic phase is washed with water and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum to give 0.65 g of the expectedproduct.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 1.9 ppm: mt: 2H 2.7 to 3.3ppm: mt: 2H 3.65 ppm: AB system: 2H 4.0 ppm: AB system: 2H 4.3 ppm: t:1H 4.45 ppm: AB system: 2H 7.0 to 7.6: u: 11H

This compound can also be obtained using the method described below.

A') 4-Benzyl-6-(3,4-dichlorophenyl)-6-(2-hydroxyethyl)morpholin-3-one

A mixture of 6 g of the compound obtained in Preparation 1.4 and 1.87 gof potassium tert-butylate in 100 ml of THF is stirred for two hours atRT, 2.85 g of benzyl bromide are then added slowly and the reactionmixture is refluxed for 3 hours. It is concentrated under vacuum, theresidue is taken up with a buffer solution of pH 2 and extracted withether, the organic phase is washed with water and dried over Na₂ SO₄ andthe solvent is evaporated off under vacuum. The product obtained isdissolved in MeOH, 1.3 g of lithium hydroxide monohydrate are added andthe reaction mixture is stirred for 30 minutes at RT. It is concentratedunder vacuum, the residue is extracted with ether, the organic phase iswashed with water and dried over Na₂ SO₄ and the solvent is evaporatedoff under vacuum. The residue is chromatographed on silica H using aDCM/MeOH mixture (100/1; v/v) as the eluent to give 4.6 g of theexpected product.

B)4-Benzyl-6-(3,4-dichlorophenyl)-6-[2-(methanesulfonyloxy)ethyl]morpholin-3-one

A solution of 0.65 g of the compound obtained in the previous step and0.34 g of triethylamine in 30 ml of DCM is cooled to 0° C. and 0.25 g ofmethanesulfonyl chloride is added. After the addition, the reactionmixture is concentrated under vacuum, the residue is extracted withAcOEt, the organic phase is washed with water and dried over Na₂ SO₄ andthe solvent is evaporated off under vacuum to give 0.71 g of theexpected product, which is used as such.

C)4-Benzyl-6-(3,4-dichlorophenyl)-6-[2-(4-hydroxy-4-phenylpiperid-1-yl)ethyl]morpholin-3-onehydrochloride hemihydrate

A mixture of 0.7 g of the compound obtained in the previous step, 0.378g of 4-hydroxy-4-phenylpiperidine and 0.8 g of K₂ CO₃ in 5 ml ofacetonitrile is refluxed for 4 hours. After cooling to RT, the reactionmixture is poured into water and extracted with AcOEt, the organic phaseis washed with water and dried over Na₂ SO₄ and the solvent isevaporated off under vacuum. The residue is chromatographed on silica Husing a DCM/MeOH mixture (100/3; v/v) as the eluent. The productobtained is dissolved in the minimum amount of DCM and acidified to pH 1by the addition of a saturated solution of gaseous HCl in ether and theprecipitate formed is wrung to give 0.43 g of the expected product.M.p.=160-162° C.

EXAMPLE 156-(3,4-Dichlorophenyl)-6-[2-(4-hydroxy-4-phenylpiperid-1-yl)ethyl]-4-(4-phenylbenzyl)morpholin-3-onehydrochloride monohydrate

A)6-[2-(Benzoyloxy)ethyl]-6-(3,4-dichlorophenyl)-4-(4-phenylbenzyl)morpholin-3-one

A mixture of 1.3 g of the compound obtained in Preparation 1.4 and 0.36g of potassium tert-butylate in 30 ml of THF is stirred for 30 minutesat RT, 0.79 g of 4-(bromomethyl)biphenyl is added and the reactionmixture is refluxed for 2 hours. It is concentrated under vacuum, theresidue is extracted with ether, the organic phase is washed with waterand dried over Na₂ SO₄ and the solvent is evaporated off under vacuum.The residue is chromatographed on silica H using DCM and then a DCM/MeOHmixture (100/0.5; v/v) as the eluent to give 1.1 g of the expectedproduct.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.3 ppm: mt: 2H 3.55 ppm:AB system: 2H 3.9 to 4.4 ppm: u: 4H 4.5 ppm: s: 2H 7.0 to 7.8 ppm: U:17H

B)6-(3,4-Dichlorophenyl)-6-(2-hydroxyethyl)-4-(4-phenylbenzyl)morpholin-3-one

A mixture of 1.1 g of the compound obtained in the previous step and 2ml of concentrated NaOH solution in 20 ml of MeOH is stirred for 30minutes at RT. The reaction mixture is concentrated under vacuum, theresidue is extracted with ether, the organic phase is washed with waterand dried over Na₂ SO₄ and the solvent is evaporated off under vacuum togive 0.84 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 1.85 ppm: mt: 2H 2.7 to 3.3ppm: mt: 2H 3.5 ppm: AB system: 2H 3.95 ppm: AB system: 2H 4.35 ppm: t:1H 4.4 ppm: AB system: 2H 7.0 to 7.6 ppm: u: 12H

C)6-(3,4-Dichlorophenyl)-6-[2-(methanesulfonyloxy)ethyl]-4-(4-phenylbenzyl)morpholin-3-one

0.252 g of methanesulfonyl chloride is added at RT to a solution of 0.84g of the compound obtained in the previous step and 0.223 g oftriethylamine in 30 ml of DCM and the mixture is stirred for 30 minutesat RT. It is concentrated under vacuum, the residue is extracted withether, the organic phase is washed with water and dried over Na₂ SO₄ andthe solvent is evaporated off under vacuum to give 0.89 g of theexpected product, which is used as such.

D)6-(3,4-Dichlorophenyl)-6-[2-(4-hydroxy-4-phenylpiperid-1-yl)ethyl]-4-(4-phenylbenzyl)morpholin-3-onehydrochloride monohydrate

A mixture of 0.89 g of the compound obtained in the previous step, 0.875g of 4-hydroxy-4-phenylpiperidine p-toluenesulfonate and 0.483 g of K₂CO₃ in 2 ml of DMF is heated at 80-100° C. for 1 hour. After cooling toRT, the reaction mixture is poured into water and extracted with ether,the organic phase is washed with water and dried over Na₂ So₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H using a gradient of a DCM/MeOH mixture (from 100/2; v/v to100/5; v/v) as the eluent. The product obtained is dissolved in theminimum amount of DCM and acidified to pH 1 by the addition of asaturated solution of gaseous HCl in ether and the precipitate formed iswrung to give 0.45 g of the expected product. M.p.=143-150° C.

EXAMPLE 166-(3,4-Dichlorophenyl)-6-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-onechloride monohydrate

A)6-[2-(Benzoyloxy)ethyl]-6-(3,4-dichlorophenyl)-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-one

A mixture of 2.1 g of the compound obtained in Preparation 1.4 and 0.616g of potassium tert-butylate in 50 ml of THF is stirred for 30 minutesat RT, 1.44 g of 3,5-bis(trifluoromethyl)benzyl chloride are added andthe reaction mixture is refluxed for 1 hour. It is concentrated undervacuum, the residue is taken up with a buffer solution of pH 4 andextracted with ether, the organic phase is washed with water and driedover Na₂ SO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica H using a DCM/MeOH mixture (100/0.5; v/v)as the eluent to give 1.8 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.4 ppm: mt: 2H 4.05 ppm:AB system: 2H 4.15 to 4.6 ppm: u: 4H 4.75 ppm: AB system: 2H 7.3 to 8.2ppm: u: 11H

B)6-(3,4-Dichlorophenyl)-6-(2-hydroxyethyl)-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-one

A mixture of 1.8 g of the compound obtained in the previous step and 4ml of concentrated NaOH solution in 30 ml of MeOH is stirred for 30minutes at 0° C. and stirring is then continued for 1 hour at RT. Thereaction mixture is concentrated under vacuum, the residue is extractedwith ether, the organic phase is washed with water and dried over Na₂SO₄ and the solvent is evaporated off under vacuum to give 1.1 g of theexpected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.0 ppm: t: 2H 2.9 to 3.45ppm: mt: 2H 3.9 ppm: AB system: 2H 4.2 ppm: AB system: 2H 4.45 ppm: t:1H 4.7 ppm: AB system: 2H 7.1 to 8.2 ppm: u: 6H

C)6-(3,4-Dichlorophenyl)-6-[2-(methanesulfonyloxy)ethyl]-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-one

0.25 g of methanesulfonyl chloride is added at RT to a solution of 1.1 gof the compound obtained in the previous step and 0.22 g oftriethylamine in 30 ml of DCM and the reaction mixture is stirred for 1hour. It is concentrated under vacuum, the residue is extracted withAcOEt, the organic phase is washed with water and dried over Na₂ SO₄ andthe solvent is evaporated off under vacuum to give 1.2 g of the expectedproduct, which is used as such.

D)6-(3,4-Dichlorophenyl)-6-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-onechloride monohydrate

A mixture of 1.2 g of the compound obtained in the previous step and0.45 g of 4-phenyl-1-azabicyclo-[2.2.2]octane in 4 ml of DMF is heatedat 100° C. for 1 hour. After cooling to RT, the reaction mixture ispoured into water and extracted with DCM, the organic phase is washedwith 2 N HCl solution, with saturated NaCl solution and with water anddried over Na₂ SO₄ and the solvent is evaporated off under vacuum togive 0.9 g of the expected product after crystallization from a DCM/isoether/pentane mixture. M.p.=160° C.

EXAMPLE 172-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-4-benzoyl-2-(3,4-dichlorophenyl)morpholinehydrochloride monohydrate

A) 4-Benzoyl-2-(3,4-dichlorophenyl)-2-(2-hydroxyethyl)morpholine

A solution of 3.6 g of the compound obtained in Preparation 1.5 and 2.9g of triethylamine in 50 ml of DCM is cooled to -60° C., a solution of1.83 g of benzoyl chloride in 20 ml of DCM is added dropwise and thereaction mixture is stirred for 30 minutes. It is concentrated undervacuum, the residue is extracted with ether, the organic phase is washedwith water and with 10% NaOH solution and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H using a gradient of a DCM/MeOH mixture (from 100/1; v/v to100/5; v/v) as the eluent to give 1.2 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 1.95 ppm: mt: 2H 2.8 to 4.8ppm: u: 9H 6.8 to 7.9 ppm: u: 8H

B)4-Benzoyl-2-(3,4-dichlorophenyl)-2-[2-(methanesulfonyloxy)ethyl]morpholine

A solution of 1.2 g of the compound obtained in the previous step and0.637 g of triethylamine in 50 ml of DCM is heated to 60° C., a solutionof 0.414 g of methanesulfonyl chloride in 10 ml of DCM is added dropwiseand the reaction mixture is stirred for 1 hour at 60° C. It isconcentrated under vacuum, the residue is extracted with an AcOEt/ethermixture (50/50; v/v), the organic phase is washed with water and withsaturated NaHCO₃ solution and dried over Na₂ SO₄ and the solvent isevaporated off under vacuum to give 1 g of the expected product, whichis used as such.

C)2-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-4-benzoyl-2-(3,4-dichlorophenyl)morpholinehydrochloride monohydrate

A mixture of 1 g of the compound obtained in the previous step, 1 g of4-acetamido-4-phenylpiperidine p-toluenesulfonate and 1 g of K₂ CO₃ in10 ml of acetonitrile and 5 ml of DMF is refluxed for 4 hours. Thereaction mixture is concentrated under vacuum, the residue is extractedwith AcOEt, the organic phase is washed with water and dried over Na₂SO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H using a DCM/MeOH mixture (100/3; v/v) as theeluent. The product obtained is dissolved in the minimum amount of DCMand acidified to pH 1 by the addition of a saturated solution of gaseousHCl in ether and the precipitate formed is wrung to give 0.4 g of theexpected product. M.p.=184-187° C.

EXAMPLE 182-(3,4-Dichlorophenyl)-4-[(3-isopropoxyphenyl)acetyl]-2-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ETHYL]morpholinechloride monohydrate

A)2-(3,4-Dichlorophenyl)-2-(2-hydroxyethyl)-4-[(3-isopropoxyphenyl)acetyl]morpholine

A solution of 1.2 g of the compound obtained in Preparation 1.5, 0.83 gof 3-isopropoxyphenylacetic acid and 0.86 g of triethylamine in 15 ml ofDCM is cooled to 0° C., 2 g of BOP are added and the reaction mixture isstirred for 30 minutes. It is concentrated under vacuum, the residue isextracted with DCM, the organic phase is washed with water, with abuffer solution of pH 2 and with water and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H using a gradient of a DCM/MeOH mixture (from 100/0.5; v/v to100/2; v/v) as the eluent to give 0.25 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 1.2 ppm: d: 6H 1.8 ppm: t:2H 2.8 to 4.8 ppm: u: 11H 6.4 to 7.8 ppm: u: 7H

B)2-(3,4-Dichlorophenyl)-4-[(3-isopropoxyphenyl)acetyl]-2-[2-(methanesulfonyloxy)ethyl]morpholine

0.069 g of methanesulfonyl chloride is added at RT to a solution of 0.25g of the compound obtained in the previous step and 0.061 g oftriethylamine in 10 ml of DCM and the reaction mixture is stirred for 30minutes. It is concentrated under vacuum, the residue is extracted withAcOEt, the organic phase is washed with water and with saturated NaClsolution and dried over Na₂ SO₄ and the solvent is evaporated off undervacuum to give 0.285 g of the expected product, which is used as such.

C)2-(3,4-Dichlorophenyl)-4-[(3-isopropoxyphenyl)acetyl]-2-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]morpholinechloride monohydrate

A mixture of 0.28 g of the compound obtained in the previous step and0.15 g of 4-phenyl-1-azabicyclo[2.2.2]octane in 2 ml of DMF is heated at100° C. for 1 hour. The reaction mixture is concentrated under vacuum,the residue is extracted with DCM, the organic phase is washed withwater, with 10% HCl solution and with saturated NaCl solution and driedover Na₂ SO₄ and the solvent is evaporated off under vacuum to give 0.17g of the expected product after crystallization from an acetone/ethermixture. M.p.=125-130° C.

EXAMPLE 192-[3-(4-Acetamido-4-phenylpiperid-1-yl)propyl]-4-benzoyl-2-(3,4-dichlorophenyl)morpholinehydrochloride monohydrate

A) 4-Benzoyl-2-(3,4-dichlorophenyl)-2-(3-hydroxypropyl)morpholine

A solution of 2 g of the compound obtained in Preparation 1.6 and 0.83 gof triethylamine in 30 ml of DCM is cooled to -10° C., a solution of0.97 g of benzoyl chloride in 10 ml of DCM is added dropwise and thereaction mixture is stirred for 30 minutes. It is concentrated undervacuum, the residue is extracted with AcOEt, the organic phase is washedwith water and with 10% NaOH solution and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H using a DCM/MeOH mixture (100/1; v/v) as the eluent to give1.7 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 1.9 to 2.2 ppm: u: 4H 3.1to 4.6 ppm: u: 9H 7.0 to 7.9 ppm: u: 8H

B)4-Benzoyl-2-(3,4-dichlorophenyl)-2-[3-(methanesulfonyloxy)propyl]morpholine

A solution of 1.7 g of the compound obtained in the previous step and0.52 g of triethylamine in 30 ml of DCM is cooled to 0° C., 0.6 g ofmethanesulfonyl chloride is added and the mixture is stirred for 30minutes. It is concentrated under vacuum, the residue is extracted withAcOEt, the organic phase is washed with water and dried over Na₂ SO₄ andthe solvent is evaporated off under vacuum to give 1.7 g of the expectedproduct, which is used as such.

C)2-[3-(4-Acetamido-4-phenylpiperid-1-yl)propyl]-4-benzoyl-2-(3,4-dichlorophenyl)morpholinehydrochloride monohydrate

A mixture of 1.7 g of the compound obtained in the previous step, 2.18 gof 4-acetamido-4-phenylpiperidine p-toluenesulfonate and 2.5 g of K₂ CO₃in 10 ml of DMF and 10 ml of acetonitrile is refluxed for 3 hours. Thereaction mixture is concentrated under vacuum, the residue is taken upwith water and extracted with ether, the organic phase is washed withwater and dried over Na₂ SO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica H using a DCM/MeOHmixture (100/3; v/v) as the eluent. The product obtained is dissolved inthe minimum amount of DCM, a saturated solution of gaseous HCl in etheris added until the pH is 1, and the precipitate formed is wrung to give1 g of the expected product. M.p.=170-173° C.

EXAMPLE 203-Benzyl-5-(3,4-dichlorophenyl)-5-[2-(4-hydroxy-4-phenylpiperid-1-yl)ethyl]oxazolidin-2-onehydrochloride

A)5-[2-(Benzoyloxy)ethyl]-3-benzyl-5-(3,4-dichlorophenyl)oxazolidin-2-one

0.44 g of potassium tert-butylate is added at RT to a solution of 1.5 gof the compound obtained in Preparation 1.7 in 30 ml of THF and themixture is stirred for 1 hour at RT. 0.667 g of benzyl bromide is thenadded dropwise and the reaction mixture is refluxed for 3 hours. It isconcentrated under vacuum, the residue is extracted with ether, theorganic phase is washed with a buffer solution of pH 2 and with waterand dried over Na₂ SO₄ and the solvent is evaporated off under vacuum.The residue is chromatographed on silica H using DCM and then a DCM/MeOHmixture (99.5/0.5; v/v) as the eluent to give 0.9 g of the expectedproduct.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.6 ppm: mt: 2H 3.5 to 4.0ppm: AB system: 2H 4.2 to 4.7 ppm: u: 4H 7.2 to 8.0 ppm: u: 13H

B) 3-Benzyl-5-(3,4-dichlorophenyl)-5-(2-hydroxyethyl)oxazolidin-2-one

A mixture of 0.9 g of the compound obtained in the previous step and 0.5ml of concentrated NaOH solution in 30 ml of MeOH and 15 ml of DCM isstirred for 30 minutes at RT. The reaction mixture is concentrated undervacuum, the residue is extracted with ether, the organic phase is washedwith water and dried over Na₂ SO₄ and the solvent is evaporated offunder vacuum to give 0.7 g of the expected product, which is used assuch.

C)3-Benzyl-5-(3,4-dichlorophenyl)-5-[2-(methanesulfonyloxy)ethyl]oxazolidin-2-one

0.24 g of methanesulfonyl chloride is added at RT to a solution of 0.7 gof the compound obtained in the previous step and 0.21 g oftriethylamine in 20 ml of DCM and the reaction mixture is stirred for 1hour at RT. It is concentrated under vacuum, the residue is extractedwith AcOEt, the organic phase is washed with water and dried over Na₂SO₄ and the solvent is evaporated off under vacuum to give 0.76 g of theexpected product, which is used as such.

D)3-Benzyl-5-(3,4-dichlorophenyl)-5-[2-(4-hydroxy-4-phenylpiperid-1-yl)ethyl]oxazolidin-2-onehydrochloride

A mixture of 0.76 g of 4-hydroxy-4-phenylpiperidine and 0.282 g ofpotassium iodide in 2 ml of DMF is heated at 50-60° C. for 3 hours.After cooling to RT, the reaction mixture is poured into water andextracted with AcOEt, the organic phase is washed with water and driedover Na₂ SO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica H using a gradient of a DCM/MeOH mixture(from 100/2; v/v to 100/3; v/v) as the eluent. The product obtained isdissolved in the minimum amount of DCM and acidified to pH 1 by theaddition of a saturated solution of gaseous HCl in ether and theprecipitate formed is wrung to give 0.36 g of the expected product.M.p.=223-225° C.

EXAMPLE 215-(3,4-Dichlorophenyl)-5-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-onechloride dihydrate

A)5-(3,4-Dichlorophenyl)-5-(2-hydroxyethyl)-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one

A mixture of 1.4 g of the compound obtained in Preparation 1.7 and 0.45g of potassium tert-butylate in 30 ml of THF is stirred for 30 minutesat RT, 1.05 g of 3,5-bis(trifluoromethyl)benzyl chloride are added andthe mixture is refluxed for 5 hours. It is concentrated under vacuum,the residue is extracted with ether, the organic phase is washed withwater and dried over MgSO₄ and the solvent is evaporated off undervacuum. The product obtained is taken up with 30 ml of MeOH, 0.18 g oflithium hydroxide monohydrate and 1 ml of water are added and themixture is stirred for 2 hours at RT. It is concentrated under vacuum,the residue is extracted with ether, the organic phase is washed withwater and dried over MgSO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica H using a DCM/MeOHmixture (100/0.5; v/v) as the eluent to give 0.96 g of the expectedproduct.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.2 ppm: mt: 2H 3.0 to 3.55ppm: mt: 2H 3.57 to 3.9 ppm: AB system: 2H 4.35 to 4.7 ppm: u: 3H 7.2 to8.1 ppm: u: 6H

B)5-(3,4-Dichlorophenyl)-5-[2-(methanesulfonyloxy)-ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one

0.24 g of methanesulfonyl chloride is added at RT to a solution of 0.95g of the compound obtained in the previous step and 0.21 g oftriethylamine in 20 ml of DCM and the reaction mixture is stirred for 1hour at RT. It is concentrated under vacuum, the residue is extractedwith AcOEt, the organic phase is washed with water and dried over Na₂SO₄ and the solvent is evaporated off under vacuum to give 1.1 g of theexpected product, which is used as such.

C)5-(3,4-Dichlorophenyl)-5-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-onechloride dihydrate

A mixture of 0.46 g of 4-phenyl-1-azabicyclo[2.2.2]octane and 1.1 g ofthe compound obtained in the previous step in 2 ml of DMF is heated at60° C. for 5 hours. After cooling to RT, the reaction mixture is pouredinto water and extracted with DCM, the organic phase is washed withwater, with saturated NaCl solution, with 2 N HCl solution and withwater and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 0.6 g of the expected product after crystallization froma DCM/pentane mixture. M.p.=127-130° C. (dec.).

EXAMPLE 225-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-1-benzyl-5-(3,4-dichlorophenyl)-4-methylpiperazine-2,3-dionehydrochloride

A)1-Benzyl-5-(3,4-dichlorophenyl)-4-methyl-5-[2-(tetrahydropyran-2-yloxy)ethyl]piperazine-2,3-dione

0.2 g of potassium tert-butylate is added to a solution of 0.6 g of thecompound obtained in Preparation 1.8 in 10 ml of THF and the mixture isstirred for 1 hour at RT. 0.21 ml of benzyl bromide is then added andthe reaction mixture is heated at 40° C. for 2 hours. It is concentratedunder vacuum, the residue is extracted with DCM, the organic phase iswashed with water and dried over MgSO₄ and the solvent is evaporated offunder vacuum to give 0.58 g of the expected product aftercrystallization from ether. M.p.=178° C.

B)1-Benzyl-5-(3,4-dichlorophenyl)-5-(2-hydroxyethyl)-4-methylpiperazine-2,3-dione

A mixture of 0.56 g of the compound obtained in the previous step, 10 mlof MeOH and 1 ml of a saturated solution of gaseous HCl in ether isstirred for 1 hour. The reaction mixture is concentrated under vacuum,the residue is taken up with iso ether and the precipitate formed iswrung to give 0.45 g of the expected product. M.p.=198° C.

C)1-Benzyl-5-(3,4-dichlorophenyl)-5-[2-(methanesulfonyloxy)ethyl]-4-methylpiperazine-2,3-dione

A solution of 0.44 g of the compound obtained in the previous step and0.24 ml of triethylamine in 10 ml of DCM is cooled to 0° C., 0.12 ml ofmethanesulfonyl chloride is added slowly and the reaction mixture isstirred for 15 minutes. It is washed twice with water, the organic phaseis dried over MgSO₄ and the solvent is evaporated off under vacuum togive 0.5 g of the expected product, which is used as such.

D)5-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-1-benzyl-5-(3,4-dichlorophenyl)-4-methylpiperazine-2,3-dionehydrochloride

A mixture of 0.5 g of the compound obtained in the previous step, 0.85 gof 4-acetamido-4-phenylpiperidine p-toluenesulfonate and 0.6 g of K₂ CO₃in 5 ml of DMF is heated at 80° C. for 8 hours 30 minutes. After coolingto RT, the reaction mixture is poured into water and the precipitateformed is wrung and washed with water. The precipitate is dissolved inDCM, the organic phase is dried over MgSO₄ and the solvent is evaporatedoff under vacuum. The residue is chromatographed on silica H using DCMand then a DCM/MeOH mixture (93/7; v/v) as the eluent. The productobtained is dissolved in DCM, acidified to pH 1 by the addition of asaturated solution of gaseous HCl in ether and concentrated under vacuumto give 0.105 g of the expected product after crystallization fromether. M.p.=220° C. (dec.).

EXAMPLE 233-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-1-benzoyl-3-(3,4-dichlorophenyl)-4-methylpiperazinedihydrochloride hemihydrate

A)1-Benzoyl-3-(3,4-dichlorophenyl)-4-methyl-3-[2-(tetrahydropyran-2-yloxy)ethyl]piperazine

0.45 ml of triethylamine is added to a solution of 1 g of the compoundobtained in Preparation 1.9 in 15 ml of DCM, the reaction mixture isthen cooled to 0° C. and 0.32 ml of benzoyl chloride is added dropwise.The reaction mixture is then washed with water and with 1 N NaOHsolution, the organic phase is dried over MgSO₄ and the solvent isevaporated off under vacuum. The residue is chromatographed on silicausing heptane and then a heptane/AcOEt mixture (50/50; v/v) as theeluent to give 0.95 g of the expected product, which is used as such.

B)1-Benzoyl-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)-4-methylpiperazinehydrochloride

A saturated solution of gaseous HCl in ether is added to a solution of0.95 g of the compound obtained in the previous step in 15 ml of MeOHuntil the pH is 1, and the mixture is left to stand for 2 hours at RT.It is concentrated under vacuum, the residue is taken up with ether andthe precipitate formed is wrung and dried to give 0.8 g of the expectedcompound.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 1.1 to 1.9 ppm: u: 2H 2.1to 5.1 ppm: u: 12H 7.1 to 8.5 ppm: u: 8H

C)3-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-1-benzoyl-3-(3,4-dichlorophenyl)-4-methylpiperazinedihydrochloride Hemihydrate

0.78 ml of triethylamine is added to a solution of 0.8 g of the compoundobtained in the previous step in 15 ml of DCM, the mixture is thencooled to -20° C. and 0.25 ml of methanesulfonyl chloride is addeddropwise. The reaction mixture is stirred for 10 minutes and then washedwith water and with 10% Na₂ CO₃ solution and the organic phase is driedover MgSO₄ and filtered. 1.5 q of 4-acetamido-4-phenylpiperidinep-toluenesulfonate are added to the filtrate and the mixture isconcentrated under vacuum. The residue is taken up with 10 ml of DMF,1.5 g of K₂ CO₃ are added and the reaction mixture is heated at 80° C.for 2 hours 30 minutes. After cooling, it is poured into iced water andextracted with AcOEt, the organic phase is washed with 1 N NaOH solutionand with water and dried over MgSO₄ and the solvent is evaporated offunder vacuum. The residue is chromatographed on silica H using DCM andthen a DCM/MeOH mixture (93/7; v/v) as the eluent. The product obtainedis taken up with a saturated solution of gaseous HCl in ether and theprecipitate formed is wrung to give 0.86 g of the expected product.M.p.=210° C. (dec.).

EXAMPLE 243-(3,4-Dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl]-4-methyl-3-[2-[4-phenyl-1-azoniabicyclo[2.2.2]-oct-1-yl]ethyl]piperazinechloride hydrochloride

A)3-(3,4-Dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl]-4-methyl-3-[2-(tetrahydropyran-2-yloxy)ethyl]piperazine

0.57 ml of triethylamine and then 0.52 g of 3-isopropoxyphenylaceticacid and 1.3 g of BOP are added to a solution of 1 g of the compoundobtained in Preparation 1.9 in 15 ml of DCM. The mixture is stirred for15 minutes at RT and concentrated under vacuum. The residue is extractedwith AcOEt, the organic phase is washed with water, with 1 N NaOHsolution and with saturated NaCl solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica using heptane and then a heptane/AcOEt mixture (50/50; v/v) asthe eluent to give 1.1 g of the expected product, which is used as such.

B)3-(3,4-Dichlorophenyl)-3-(2-hydroxyethyl)-1-[(3-isopropoxyphenyl)acetyl]-4-methylpiperazinehydrochloride

A saturated solution of gaseous HCl in ether is added to a solution of1.1 g of the compound obtained in the previous step in 15 ml of MeOHuntil the pH is 1, and the reaction mixture is left to stand for 2 hours30 minutes at RT. It is concentrated under vacuum, the residue is takenup with ether and the precipitate formed is wrung and dried to give 1.05g of the expected product.

C)3-(3,4-Dichlorophenyl)-1-[(3-isopropoxyphenyl)acetyl]-4-methyl-3-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]piperazinechloride hydrochloride

0.8 ml of triethylamine is added to a solution of 1.05 g of the compoundobtained in the previous step in 15 ml of DCM, the mixture is thencooled to -20° C. and 0.22 ml of methanesulfonyl chloride is addeddropwise. After 5 minutes, the reaction mixture is washed with water andwith 10% Na₂ CO₃ solution and the organic phase is dried over MgSO₄ andfiltered. 1 g of 4-phenylquinuclidine is then added to the filtrate andthe mixture is concentrated under vacuum. The residue is taken up with 1ml of DMF and heated at 80° C. for 1 hour. After cooling to RT, thereaction mixture is diluted with DCM and washed twice with 2 N HClsolution and with saturated NaCl solution, the organic phase is driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica H using DCM and then a DCM/MeOH mixture(90/10; v/v) as the eluent. The product obtained is taken up with isoether and the precipitate formed is wrung to give 1.05 g of the expectedproduct. M.p.=168° C. (dec.).

EXAMPLE 256-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-4-benzyl-6-(3,4-difluorophenyl)morpholin-3-onehydrochloride hemihydrate

A)6-[2-(Benzoyloxy)ethyl]-4-benzyl-6-(3,4-difluorophenyl)morpholin-3-one

A mixture of 1.1 g of the compound obtained in Preparation 1.10 and 0.38g of potassium tert-butylate in 50 ml of THF is stirred for 30 minutesat RT, 0.51 g of benzyl bromide is added and the reaction mixture isrefluxed for 2 hours. It is concentrated under vacuum, the residue isextracted with ether, the organic phase is washed with water and with abuffer solution of pH 2 and dried over Na₂ SO₄ and the solvent isevaporated off under vacuum. The residue is chromatographed on silica Husing DCM and then a DCM/MeOH mixture (100/2; v/v) as the eluent to give0.6 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.3 ppm: mt: 2H 3.75 ppm:AB system: 2H 3.9 to 4.4 ppm: u: 4H 4.5 ppm: s: 2H 7.0 to 8.0 ppm: u:13H

B) 4-Benzyl-6-(3,4-difluorophenyl)-6-(2-hydroxyethyl)morpholin-3-one

A mixture of 0.6 g of the compound obtained in the previous step and 0.5ml of concentrated NaOH solution in 10 ml of MeOH is stirred for 30minutes at RT. The reaction mixture is concentrated under vacuum, theresidue is extracted with AcOEt, the organic phase is washed with waterand dried over Na₂ SO₄ and the solvent is evaporated off under vacuum togive 0.42 g of the expected product, which is used as such.

C)4-Benzyl-6-(3,4-difluorophenyl)-6-[2-(methanesulfonyloxy)ethyl]morpholin-3-one

0.137 g of methanesulfonyl chloride is added at RT to a solution of 0.42g of the compound obtained in the previous step and 0.146 g oftriethylamine in 20 ml of DCM and the mixture is stirred for 30 minutesat RT. It is concentrated under vacuum, the residue is extracted withether, the organic phase is washed with water and dried over Na₂ SO₄ andthe solvent is evaporated off under vacuum to give 0.49 g of theexpected product, which is used as such.

D)6-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-4-benzyl-6-(3,4-difluorophenyl)morpholin-3-onehydrochloride hemihydrate

A mixture of 0.49 g of the compound obtained in the previous step, 0.94g of 4-acetamido-4-phenylpiperidine p-toluenesulfonate and 0.48 g of K₂CO₃ in 1 ml of DMF is heated at 80° C. for 2 hours. After cooling to RT,the reaction mixture is poured into water and extracted with AcOEt, theorganic phase is washed with water and dried over Na₂ SO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H using a DCM/MeOH mixture (100/3; v/v) as the eluent. Theproduct obtained is dissolved in the minimum amount of DCM and acidifiedto pH 1 by the addition of a saturated solution of gaseous HCl in etherand the precipitate formed is wrung to give 0.5 g of the expectedproduct. M.p.=273-275° C.

EXAMPLE 266-(3,4-Difluorophenyl)-6-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-onechloride dihydrate

A)6-[2-(Benzoyloxy)ethyl]-6-(3,4-difluorophenyl)-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-one

A mixture of 1 g of the compound obtained in Preparation 1.10 and 0.32 gof potassium tert-butylate in 20 ml of THF is stirred for 1 hour at RT,0.735 g of 3,5-bis(trifluoromethyl)benzyl chloride is then added and thereaction mixture is refluxed for 5 hours. It is concentrated undervacuum, the residue is extracted with ether, the organic phase is washedwith water and dried over MgSO₄ and the solvent is evaporated off undervacuum to give the expected product, which is used as such.

B)6-(3,4-Difluorophenyl)-6-(2-hydroxyethyl)-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-one

The product obtained in the previous step is dissolved in 15 ml of MeOH,0.235 g of lithium hydroxide monohydrate is added and the reactionmixture is stirred for 30 minutes at RT. It is concentrated undervacuum, the residue is extracted with ether, the organic phase is washedwith water and dried over MgSO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica H using a DCM/MeOHmixture (100/1; v/v) as the eluent to give 0.84 g of the expectedproduct.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 1.95 ppm: t: 2H 2.95 to 3.5ppm: mt: 2H 3.95 ppm: AB system: 2H 4.25 ppm: AB system: 2H 4.5 ppm: t:1H 4.7 ppm: AB system: 2H 7.0 to 8.2 ppm: u: 6H

C)6-(3,4-Difluorophenyl)-6-[2-(methanesulfonyloxy)ethyl]-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-one

0.22 g of methanesulfonyl chloride is added at RT to a solution of 0.8 gof the compound obtained in the previous step and 0.2 g of triethylaminein 15 ml of DCM and the reaction mixture is stirred for 30 minutes atRT. It is concentrated under vacuum, the residue is extracted withAcOEt, the organic phase is washed with water and dried over MgSO₄ andthe solvent is evaporated off under vacuum to give 0.9 g of the expectedproduct, which is used as such.

D)6-(3,4-Difluorophenyl)-6-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-onechloride dihydrate

A mixture of 0.9 g of the compound obtained in the previous step and0.38 g of 4-phenyl-1-azabicyclo[2.2.2]octane in 2 ml of DMF is heated at80° C. for 4 hours. After cooling to RT, the reaction mixture is pouredinto water and extracted with AcOEt, the organic phase is washed with 2N HCl solution, with water, with saturated NaCl solution and with waterand dried over Na₂ SO₄ and the solvent is evaporated off under vacuum togive 0.41 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.0 to 2.6 ppm: u: 8H 2.7to 3.7 ppm: u: 8H 3.9 ppm: AB system: 2H 4.1 to 5.1 ppm: u: 4H 7.0 to8.2 ppm: u: 11H

EXAMPLE 272-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-4-benzoyl-2-(3,4-difluorophenyl)morpholinehydrochloride monohydrate

A) 4-Benzoyl-2-(3,4-difluorophenyl)-2-(2-hydroxyethyl)morpholine

A solution of 0.9 g of benzoyl chloride in 20 ml of DCM is addeddropwise at RT to a solution of 0.77 g of the compound obtained inPreparation 1.11 and 0.7 g of triethylamine in 30 ml of DCM and thereaction mixture is stirred for 1 hour at RT. It is concentrated undervacuum, the residue is extracted with ether, the organic phase is washedwith water and the solvent is evaporated off under vacuum. The residueis dissolved in MeOH, 0.53 g of lithium hydroxide monohydrate is addedand the reaction mixture is stirred for 30 minutes at RT. It isconcentrated under vacuum, the residue is extracted with DCM, theorganic phase is washed with water and dried over MgSO₄ and the solventis evaporated off under vacuum. The residue is chromatographed on silicaH using a DCM/MeOH mixture (100/0.5; v/v) as the eluent to give 0.5 g ofthe expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 1.95 ppm: mt: 2H 2.8 to 4.9ppm: u: 9H 6.8 to 7.8 ppm: u: 8H

B)4-Benzoyl-2-(3,4-difluorophenyl)-2-[2-(methanesulfonyloxy)ethyl]morpholine

A solution of 0.19 g of methanesulfonyl chloride in 5 ml of DCM is addeddropwise at RT to a solution of 0.5 g of the compound obtained in theprevious step and 0.17 g of triethylamine in 20 ml of DCM and thereaction mixture is stirred for 1 hour at RT. It is concentrated undervacuum, the residue is extracted with AcOEt, the organic phase is washedwith water and dried over Na₂ SO₄ and the solvent is evaporated offunder vacuum to give 0.56 g of the expected product, which is used assuch.

C)2-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-4-benzoyl-2-(3,4-difluorophenyl)morpholinehydrochloride monohydrate

A mixture of 0.56 g of the compound obtained in the previous step, 1 gof 4-acetamido-4-phenylpiperidine p-toluenesulfonate and 0.7 g of K₂ CO₃in 2 ml of DMF is heated at 80° C. for 3 hours. The reaction mixture ispoured into water and extracted with AcOEt, the organic phase is washedwith water and dried over Na₂ SO₄ and the solvent is evaporated offunder vacuum. The residue is chromatographed on silica H using aDCM/MeOH mixture (100/3; v/v) as the eluent. The product obtained isdissolved in the minimum amount of DCM, acidified to pH 1 by theaddition of a saturated solution of gaseous HCl in ether andconcentrated under vacuum to give 0.4 g of the expected product aftercrystallization from an EtOH/ether mixture. M.p.=179-182° C.

EXAMPLE 285-(3,4-Difluorophenyl)-5-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-onechloride 1.5 hydrate

A)5-(3,4-Difluorophenyl)-5-(2-hydroxyethyl)-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one

A mixture of 1.5 g of the compound obtained in Preparation 1.12 and 0.48g of potassium tert-butylate in 15 ml of THF is stirred for 1 hour atRT, 1.1 g of 3,5-bis(trifluoromethyl)benzyl chloride are added and themixture is refluxed for 5 hours. It is concentrated under vacuum, theresidue is taken up with a buffer solution of pH 2 and extracted withether, the organic phase is washed with water and dried over MgSO₄ andthe solvent is evaporated off under vacuum. The product obtained istaken up with 20 ml of MeOH, 0.2 g of lithium hydroxide monohydrate isadded and the mixture is stirred for 30 minutes at RT. It isconcentrated under vacuum, the residue is extracted with DCM, theorganic phase is washed with water and dried over MgSO₄ and the solventis evaporated off under vacuum. The residue is chromatographed on silicaH using a DCM/MeOH mixture (100/1; v/v) as the eluent to give 1.3 g ofthe expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.2 ppm: mt: 2H 3.0 to 3.55ppm: mt: 2H 3.75 ppm: AB system: 2H 4.4 to 4.6 ppm: u: 3H 7.1 to 8.2ppm: u: 6H

B)5-(3,4-Difluorophenyl)-5-[2-(methanesulfonyloxy)ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one

0.34 g of methanesulfonyl chloride is added at RT to a solution of 1.3 gof the compound obtained in the previous step and 0.3 g of triethylaminein 20 ml of DCM and the reaction mixture is stirred for 30 minutes atRT. It is concentrated under vacuum, the residue is extracted withAcOEt, the organic phase is washed with water and dried over Na₂ SO₄ andthe solvent is evaporated off under vacuum to give 1.1 g of the expectedproduct, which is used as such.

C)5-(3,4-Difluorophenyl)-5-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-onechloride 1.5 hydrate

A mixture of 0.46 g of 4-phenyl-1-azabicyclo[2.2.2]octane and 1.1 g ofthe compound obtained in the previous step in 2 ml of DMF is heated at60° C. for 5 hours. After cooling to RT, the reaction mixture is pouredinto water and extracted with DCM, the organic phase is washed withwater, with saturated NaCl solution, with 2 N HCl solution and withwater and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 0.6 g of the expected product.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.1 ppm: mt: 6H 2.7 ppm: t:2H 2.85 to 4.0 ppm: u: 10H 4.6 ppm: AB system: 2H 7.1 to 8.2 ppm: u: 11H

EXAMPLE 294-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-1-benzyl-4-(3,4-dichlorophenyl)-3-methylimidazolidin-2-onehydrochloride

A)1-Benzyl-4-(3,4-dichlorophenyl)-3-methyl-4-[2-(tetrahydropyran-2-yloxy)ethyl]imidazolidin-2-one

0.5 g of potassium tert-butylate is added to a solution of 1.45 g of thecompound obtained in Preparation 1.13 in 20 ml of THF and the mixture isstirred for 1 hour at RT. 0.48 ml of benzyl bromide is then added andthe reaction mixture is stirred for 30 minutes at RT. It is concentratedunder vacuum, the residue is extracted with ether, the organic phase iswashed with water and dried over MgSO₄ and the solvent is concentratedunder vacuum. The residue is chromatographed on silica using heptane andthen a heptane/AcOEt mixture (40/60; v/v) as the eluent to give 1.5 g ofthe expected product, which is used as such.

B)1-Benzyl-4-(3,4-dichlorophenyl)-4-(2-hydroxyethyl)-3-methylimidazolidin-2-one

A saturated solution of gaseous HCl in ether is added to a solution of1.5 g of the compound obtained in the previous step in 20 ml of MeOHuntil the pH is 1, and the reaction mixture is stirred for 30 minutes atRT. It is concentrated under vacuum, the residue is taken up with MeOHand the solvent is evaporated off under vacuum to give 1.05 g of theexpected product after crystallization from iso ether. M.p.=118° C.

C)1-Benzyl-4-(3,4-dichlorophenyl)-4-[2-(methanesulfonyloxy)ethyl]-3-methylimidazolidin-2-one

A solution of 0.5 g of the compound obtained in the previous step and0.34 ml of triethylamine in 10 ml of DCM is cooled to 0° C., 0.17 ml ofmethanesulfonyl chloride is added and the reaction mixture is stirredfor 15 minutes. It is washed with water, the organic phase is dried overMgSO₄ and the solvent is evaporated off under vacuum to give theexpected product, which is used as such.

D)4-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-1-benzyl-4-(3,4-dichlorophenyl)-3-methylimidazolidin-2-onehydrochloride

A mixture of the compound obtained in the previous step, 0.8 g of4-acetamido-4-phenylpiperidine p-toluenesulfonate and 0.8 g of K₂ CO₃ in5 ml of DMF is heated at 80° C. for 3 hours. After cooling to RT, thereaction mixture is poured into water and extracted with AcOEt, theorganic phase is washed with 1 N NaOH solution and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica H using DCM and then aDCM/MeOH mixture (95/5; v/v) as the eluent. The product obtained isdissolved in the minimum amount of DCM, acidified to pH 1 by theaddition of a saturated solution of gaseous HCl in ether andconcentrated under vacuum to give 0.3 g of the expected product aftercrystallization from iso ether. M.p.=206° C.

EXAMPLE 304-(3,4-Dichlorophenyl)-4-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-3-methyl-1-[3,5-bis(trifluoromethyl)benzyl]imidazolidin-2-onechloride

A)4-(3,4-Dichlorophenyl)-3-methyl-4-[2-(tetrahydropyran-2-yloxy)ethyl]-1-[3,5-bis(trifluoromethyl)benzyl]imidazolidin-2-one

A mixture of 1.45 g of the compound obtained in Preparation 1.13 and 0.5g of potassium tert-butylate in 20 ml of THF is stirred for 1 hour atRT, 1.04 g of 3,5-bis(trifluoromethyl)benzyl chloride are then added andthe reaction mixture is stirred for 2 hours at RT. It is concentratedunder vacuum, the residue is extracted with ether, the organic phase iswashed with water and with saturated NaCl solution and dried over MgSO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on silica using heptane and then a heptane/AcOEt mixture(50/50; v/v) as the eluent to give 2.1 g of the expected product, whichis used as such.

B)4-(3,4-Dichlorophenyl)-4-(2-hydroxyethyl)-3-methyl-1-[3,5-bis(trifluoromethyl)benzyl]imidazolidin-2-one

1 ml of a saturated solution of gaseous HCl in ether is added to asolution of 2.1 g of the compound obtained in the previous step in 20 mlof MeOH and the mixture is stirred for 30 minutes at RT. It isconcentrated under vacuum, the residue is taken up with MeOH and thesolvent is evaporated off under vacuum to give 1.7 g of the expectedproduct after crystallization from an iso ether/pentane mixture.M.p.=96° C.

C)4-(3,4-Dichlorophenyl)-4-[2-(methanesulfonyloxy)ethyl]-3-methyl-1-[3,5-bis(trifluoromethyl)benzyl]-imidazolidin-2-one

A solution of 0.56 g of the compound obtained in the previous step and0.3 ml of triethylamine in 10 ml of DCM is cooled to 0° C., 0.15 ml ofmethanesulfonyl chloride is added and the reaction mixture is stirredfor 15 minutes. It is washed with water, the organic phase is dried overMgSO₄ and the solvent is evaporated off under vacuum to give theexpected product, which is used as such.

D)4-(3,4-Dichlorophenyl)-4-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-3-methyl-1-[3,5-bis(trifluoromethyl)benzyl]imidazolidin-2-onechloride

A mixture of the compound obtained in the previous step and 0.35 g of4-phenyl-1-azabicyclo[2.2.2]octane in 1 ml of DMF is heated at 80° C.for 3 hours. After cooling to RT, the reaction mixture is poured into amixture of 50 ml of water, 50 ml of DCM and 3 ml of concentrated HCl andstirred for 5 minutes. The precipitate formed is wrung, washed withwater, with DCM and then with ether and dried to give 0.3 g of theexpected product. M.p.=290° C.

EXAMPLE 31

6-[3-(4-Acetamido-4-phenylpiperid-1-yl)propyl]-4-benzyl-6-(3,4-dichlorophenyl)morpholin-3-onehydrochloride

A)4-Benzyl-6-[3-(benzoyloxy)propyl]-6-(3,4-dichlorophenyl)morpholin-3-one

0.369 g of potassium tert-butylate is added to a solution of 1.34 g ofthe compound obtained in Preparation 1.14 in 20 ml of THF and themixture is stirred for 1 hour at RT. 0.564 g of benzyl bromide is thenadded and the reaction mixture is refluxed for 2 hours. It isconcentrated under vacuum, the residue is taken up with a buffersolution of pH 2 and extracted with ether, the organic phase is washedwith water and dried over MgSO₄ and the solvent is evaporated off undervacuum to give the expected product, which is used as such.

B) 4-Benzyl-6-(3,4-dichlorophenyl)-6-(3-hydroxypropyl)morpholin-3-one

0.277 g of lithium hydroxide monohydrate is added to a solution of thecompound obtained in the previous step in 20 ml of MeOH and the mixtureis stirred for 1 hour at RT. It is concentrated under vacuum, theresidue is extracted with ether, the organic phase is washed with waterand dried over MgSO₄ and the solvent is evaporated off under vacuum togive 0.9 g of the expected product, which is used as such.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 0.9 to 2.1 ppm: u: 4H 3.3ppm: q: 2H 3.7 ppm: AB system: 2H 4.15 ppm: AB system: 2H 4.4 ppm: t: 1H4.5 ppm: AB system: 2H 7.1 to 7.8 ppm: u: 8H

C)4-Benzyl-6-(3,4-dichlorophenyl)-6-[3-(methanesulfonyloxy)propyl]morpholin-3-one

0.316 g of methanesulfonyl chloride is added at RT to a solution of 0.9g of the compound obtained in the previous step and 0.288 g oftriethylamine in 50 ml of DCM and the mixture is stirred for 30 minutesat RT. It is concentrated under vacuum, the residue is extracted withAcOEt, the organic phase is washed with water and dried over MgSO₄ andthe solvent is evaporated off under vacuum to give 1.08 g of theexpected product, which is used as such.

D)6-[3-(4-Acetamido-4-phenylpiperid-1-yl)propyl]-4-benzyl-6-(3,4-dichlorophenyl)morpholin-3-onehydrochloride

A mixture of 1.08 g of the compound obtained in the previous step, 1.4 gof 4-acetamido-4-phenylpiperidine p-toluenesulfonate and 1.3 g of K₂ CO₃in 5 ml of DMF is heated at 80° C. for 3 hours. After cooling, thereaction mixture is poured into water and extracted with AcOEt, theorganic phase is washed with water and dried over MgSO₄ and the solventis evaporated off under vacuum. The residue is chromatographed on silicaH using a DCM/MeOH mixture (100/3; v/v) as the eluent. The productobtained is dissolved in DCM, a saturated solution of gaseous HCl inether is added until the pH is 1, and the solvent is evaporated offunder vacuum to give 0.6 g of the expected product after crystallizationfrom an EtOH/ether mixture. M.p.=151-153° C.

EXAMPLE 324-(3,4-Dichlorophenyl)-3-methyl-4-[2-(4-phenylpiperid-1-yl)ethyl]-1-[3,5-bis(trifluoromethyl)benzyl]imidazolidin-2-onehydrochloride

A mixture of 0.55 g of the compound obtained in step C of EXAMPLE 30,0.47 g of 4-phenylpiperidine and 0.5 g of K₂ CO₃ in 4 ml of DMF isheated at 80° C. for 5 hours. After cooling, the reaction mixture ispoured into iced water and extracted with AcOEt, the organic phase iswashed with 1 N NaOH solution and with water and dried over MgSO₄ andthe solvent is evaporated off under vacuum. The residue ischromatographed on silica H using DCM and then a DCM/MeOH mixture (98/2;v/v) as the eluent. The product obtained is dissolved in ether, asaturated solution of gaseous HCl in ether is added until the pH is 1,and the precipitate formed is wrung to give 0.25 g of the expectedproduct. M.p.=208° C.

EXAMPLE 334-Benzyl-6-(3,4-dichlorophenyl)-6-[2-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]ethyl]morpholin-3-onehydrochloride monohydrate

A mixture of 0.98 g of the compound obtained in step B of EXAMPLE 14,0.645 g of 4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperidine and 0.69 g ofK₂ CO₃ in 3 ml of DMF is heated at 80° C. for 2 hours. After cooling toRT, the reaction mixture is poured into water and extracted with anAcOEt/ether mixture, the organic phase is washed with water and driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica H using a DCM/MeOH mixture (100/2; v/v) asthe eluent. The product obtained is dissolved in the minimum amount ofDCM and acidified to pH 1 by the addition of a saturated solution ofgaseous HCl in ether and the precipitate formed is wrung to give 0.42 gof the expected product. M.p.=155-178° C.

EXAMPLE 346-[2-[4-(Acetyl-N-methylamino)-4-phenylpiperid-1-yl]ethyl]-4-benzyl-6-(3,4-dichlorophenyl)morpholin-3-onehydrochloride monohydrate

A mixture of 1.1 g of the compound obtained in step B of EXAMPLE 14,1.85 g of 4-(acetyl-N-methylamino)-4-phenylpiperidine p-toluenesulfonateand 1.3 g of K₂ CO₃ in 3 ml of DMF is heated at 80-100° C. for 2 hours.After cooling to RT, the reaction mixture is poured into water andextracted with ether, the organic phase is washed with water and driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica H using a DCM/MeOH mixture (from 100/1; v/vto 100/4; v/v) as the eluent. The product obtained is dissolved in DCM,a saturated solution of hydrochloric acid in ether is added until the pHis 1, and the precipitate formed is wrung to give 0.62 g of the expectedproduct. M.p.=148-150° C.

EXAMPLE 354-Benzyl-6-[2-[4-(ethoxycarbonylamino)-4-phenylpiperid-1-yl]ethyl]-6-(3,4-dichlorophenyl)morpholin-3-onehydrochloride monohydrate

A mixture of 1.1 g of the compound obtained in step B of EXAMPLE 14, 1 gof 4-(ethoxycarbonylamino)-4-phenylpiperidine trifluoroacetate and 0.7 gof K₂ CO₃ in 3 ml of DMF is heated at 80-100° C. for 2 hours. Aftercooling to RT, the reaction mixture is poured into water and stirred for30 minutes and the precipitate formed is wrung, washed with water anddried under vacuum at 60° C. The precipitate is chromatographed onsilica H using a DCM/MeOH mixture (from 100/1; v/v to 100/4.5; v/v) asthe eluent. The product obtained is dissolved in DCM, a saturatedsolution of hydrochloric acid in ether is added until the pH is 1, andthe precipitate formed is wrung to give 0.52 g of the expected product.M.p.=148-150° C.

EXAMPLE 364-Benzoyl-2-(3,4-difluorophenyl)-2-[2-[4-(N',N'-dimethylureido)-4-phenylpiperid-1-yl]ethyl]morpholinehydrochloride monohydrate, (-) isomer

A) 4-Benzoyl-2-[2-(benzoyloxy)ethyl]-2-(3,4-difluorophenyl)morpholine,(-) isomer

A solution of 8.9 g of the compound obtained in Preparation 1.17 ((-)isomer) and 3 g of triethylamine in 100 ml of DCM is cooled to 0° C., asolution of 3.59 g of benzoyl chloride in 20 ml of DCM is added dropwiseand the reaction mixture is stirred for 30 minutes. It is concentratedunder vacuum, the residue is extracted with ether, the organic phase iswashed with water and dried over MgSO₄ and the solvent is evaporated offunder vacuum. The residue is chromatographed on silica H using aDCM/MeOH mixture (100/0.5; v/v) as the eluent to give 9.3 g of theexpected product.

[α]_(D) ²⁰ =-4.7° (c=1; MeOH)

B) 4-Benzoyl-2-(3,4-difluorophenyl)-2-(2-hydroxyethyl)morpholine, (-)isomer

6.6 g of 30% aqueous NaOH solution are added dropwise at RT to asolution of 11.5 g of the compound obtained in the previous step in 60ml of MeOH and the reaction mixture is stirred for 1 hour. It isconcentrated under vacuum, the residue is taken up with water andextracted with ether, the organic phase is washed with water and driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica H using a DCM/MeOH mixture (from 100/1; v/vto 100/5; v/v) as the eluent to give 8.4 g of the expected product aftercrystallization from iso ether. M.p.=80° C.

[α]_(D) ²⁰ =-56.1° (c=1; MeOH)

C)4-Benzoyl-2-(3,4-difluorophenyl)-2-[2-(methanesulfonyloxy)ethyl]morpholine,(-) isomer

A solution of 0.36 g of methanesulfonyl chloride in 3 ml of DCM is addeddropwise at RT to a solution of 1 g of the compound obtained in theprevious step and 0.3 g of triethylamine in 25 ml of DCM and thereaction mixture is stirred for 30 minutes at RT. It is concentratedunder vacuum, the residue is extracted with ether, the organic phase iswashed with water, with saturated NaHCO₃ solution and with water anddried over MgSO₄ and the solvent is evaporated off under vacuum to give1.05 g of the expected product.

[α]_(D) ²⁰ =-36.1° (c=1; MeOH)

D)4-Benzoyl-2-(3,4-difluorophenyl)-2-[2-[4-(N',N'-dimethylureido)-4-phenylpiperid-1-yl]ethyl]morpholinehydrochloride monohydrate, (-) isomer

2 g of the compound obtained in Preparation 2.2 are dissolved in water,rendered alkaline by the addition of concentrated NaOH solution andextracted with DCM, the organic phase is dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 1.08 g of the free base.The product obtained is taken up with 3 ml of DMF, 0.95 g of thecompound obtained in the previous step is added and the reaction mixtureis heated at 80° C. for 3 hours. After cooling, it is poured into waterand the precipitate formed is wrung and washed with water. Theprecipitate is dissolved in DCM, the organic phase is washed with 10%NaOH solution and dried over MgSO₄ and the solvent is evaporated offunder vacuum. The residue is chromatographed on silica H using aDCM/MeOH mixture (from 100/1; v/v to 100/7.5; v/v) as the eluent. Theproduct obtained is dissolved in DCM, a saturated solution ofhydrochloric acid in ether is added until the pH is 1, and the solventsare evaporated off under vacuum to give 0.3 g of the expected productafter crystallization from a DCM/pentane mixture. M.p.=168-172° C.

[α]_(D) ²⁰ =-22.2° (c=1; MeOH)

EXAMPLE 374-Benzoyl-2-(3,4-difluorophenyl)-2-[2-[4-(N',N'-dimethylureido)-4-phenylpiperid-1-yl]ethyl]morpholinehydrochloride hemihydrate, (+) isomer

A) 4-Benzoyl-2-[2-(benzoyloxy)ethyl]-2-(3,4-difluorophenyl)morpholine,(+) isomer

A solution of 20 g of the compound obtained in Preparation 1.18 ((+)isomer) and 8 ml of triethylamine in 200 ml of DCM is cooled to 0° C., 6ml of benzoyl chloride are added dropwise and the reaction mixture isstirred for 15 minutes. It is concentrated under vacuum, the residue isextracted with ether, the organic phase is washed with water, with 1 NHCl solution and with 10% Na₂ CO₃ solution and dried over MgSO₄ and thesolvent is evaporated off under vacuum to give 22 g of the expectedproduct in the form of an oil.

[α]_(D) ²⁰ =+4.7° (c=1; MeOH)

B) 4-Benzoyl-2-(3,4-difluorophenyl)-2-(2-hydroxyethyl)morpholine, (+)isomer

A mixture of 22 g of the compound obtained in the previous step, 9 ml of30% aqueous NaOH solution and 200 ml of 95° EtOH is stirred for 1 hourat RT. The reaction mixture is concentrated under vacuum, the residue isextracted with ether, the organic phase is washed three times with waterand dried over MgSO₄ and the solvent is evaporated off under vacuum togive 13.7 g of the expected product after crystallization from anether/iso ether mixture. M.p.=80° C.

[α]_(D) ²⁰ =+59.5° (c=1; MeOH)

C)4-Benzoyl-2-(3,4-difluorophenyl)-2-[2-(methanesulfonyloxy)ethyl]morpholine,(+) isomer

A solution of 1 g of the compound obtained in the previous step and 0.45ml of triethylamine in 10 ml of DCM is cooled to 0° C., 0.25 ml ofmethanesulfonyl chloride is added and the reaction mixture is stirredfor 15 minutes. It is washed with water and with 10% Na₂ CO₃ solution,the organic phase is dried over MgSO₄ and the solvent is evaporated offunder vacuum to give 1.2 g of the expected product in the form of anoil.

D)4-Benzoyl-2-(3,4-difluorophenyl)-2-[2-[4-(N',N'-dimethylureido)-4-phenylpiperid-1-yl]ethyl]morpholinehydrochloride hemihydrate, (+) isomer

A mixture of 1.2 g of the compound obtained in the previous step, 3 g ofthe compound obtained in Preparation 2.2 and 2 g of K₂ CO₃ in 10 ml ofDMF is heated at 80° C. for 3 hours. The reaction mixture is poured intoiced water and extracted with AcOEt, the organic phase is washed with 1N NaOH solution and with saturated NaCl solution and dried over MgSO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4;v/v) as the eluent. The product obtained is dissolved in DCM, asaturated solution of gaseous HCl in ether is added until the pH is 1,and the solvent is evaporated off under vacuum to give 0.66 g of theexpected product after crystallization from iso ether.

[α]_(D) ²⁰ =+22.2° (c=1; MeOH)

EXAMPLE 385-(3,4-Dichlorophenyl)-5-[2-(4-phenylpiperid-1-yl)ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-onehydrochloride

A mixture of 1.5 g of the compound obtained in step B of EXAMPLE 21 and1.03 g of 4-phenylpiperidine in 3 ml of DMF is heated at 80° C. for 3hours. After cooling, the reaction mixture is poured into water andextracted with AcOEt, the organic phase is washed with water and driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica H using a DCM/MeOH mixture (100/1; v/v) asthe eluent. The product obtained is dissolved in DCM, a saturatedsolution of gaseous HCl in ether is added until the pH is 1, and thesolvent is evaporated off under vacuum to give 0.7 g of the expectedproduct after crystallization from a DCM/pentane mixture. M.p.=112-114°C.

EXAMPLE 395-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-5-(3,4-dichlorophenyl)-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one hydrochloride monohydrate

A mixture of 1.5 g of the compound obtained in step B of EXAMPLE 21, 1.5g of 4-acetamido-4-phenylpiperidine p-toluenesulfonate and 1.6 g of K₂CO₃ in 4 ml of DMF is heated at 80° C. for 3 hours. After cooling, thereaction mixture is poured into water and extracted with an AcOEt/ethermixture (50/50; v/v), the organic phase is washed with water and driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica H using a DCM/MeOH mixture (100/3; v/v) asthe eluent. The product obtained is dissolved in DCM, a saturatedsolution of gaseous HCl in ether is added until the pH is 1, and thesolvent is evaporated off under vacuum to give 0.66 g of the expectedproduct after crystallization from a DCM/pentane mixture. M.p.=165-170°C.

EXAMPLE 405-[2-[4-Benzyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-5-(3,4-dichlorophenyl)-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-onechloride monohydrate

A mixture of 1.4 g of the compound obtained in step B of EXAMPLE 21 and0.6 g of 4-benzylquinuclidine in 3 ml of DMF is heated at 80° C. for 2hours. After cooling to RT, the reaction mixture is poured into waterand extracted with AcoEt, the organic phase is washed with water, with300 ml of 10% HCl solution and with 300 ml of saturated NaCl solutionand dried over MgSO₄ and the solvent is evaporated off under vacuum togive 1.35 g of the expected product after crystallization from AcOEt.M.p.=172-175° C.

EXAMPLE 414-Benzyl-6-(3,4-dichlorophenyl)-6-[2-[4-phenyl-4-(pyrrolidin-1-ylcarbonylamino)piperid-1-yl]ethyl]morpholin-3-onehydrochloride monohydrate

A mixture of 1.1 g of the compound obtained in step B of EXAMPLE 14, 1.2g of 4-phenyl-4-(pyrrolidin-1-ylcarbonylamino)piperidinebenzenesulfonate and 0.95 g of K₂ CO₃ in 3 ml of DMF is heated at80-100° C. for 3 hours. After cooling to RT, the reaction mixture ispoured into water and the precipitate formed is wrung, washed with waterand dried under vacuum. The precipitate is chromatographed on silica Husing a DCM/MeOH mixture (from 100/2; v/v to 100/3; v/v) as the eluent.The product obtained is dissolved in the minimum amount of DCM andacidified to pH 1 by the addition of a saturated solution of gaseous HClin ether and the precipitate formed is wrung to give 0.54 g of theexpected product. M.p.=158-160° C.

EXAMPLE 424-Benzyl-6-(3,4-dichlorophenyl)-6-[2-[4-(2-dimethylaminothiazol-4-yl)-4-phenylpiperid-1-yl]ethyl]morpholin-3-onedihydrochloride

This compound is prepared by the procedure described in EXAMPLE 41 from1.1 g of the compound obtained in step B of EXAMPLE 14, 1.3 g of4-[2-(dimethylamino)thiazol-4-yl]-4-phenylpiperidine p-toluenesulfonate,0.97 g of K₂ CO₃ and 4 ml of DMF to give 0.76 g of the expected product.M.p.=155-160° C.

EXAMPLE 434-Benzoyl-2-(3,4-dichlorophenyl)-2-[2-[4-(morpholin-4-ylcarbonylamino)-4-phenylpiperid-1-yl]ethyl]morpholinehydrochloride monohydrate

A) 4-Benzoyl-2-[2-(benzoyloxy)ethyl]-2-(3,4-dichlorophenyl)morpholine

2.03 g of benzoyl chloride are added dropwise at RT to a solution of 5 gof the compound obtained in Preparation 1.19 and 1.4 g of triethylaminein 100 ml of DCM and the reaction mixture is stirred for 30 minutes atRT. It is concentrated under vacuum, the residue is extracted withether, the organic phase is washed with water and dried over MgSO₄ andthe solvent is evaporated off under vacuum. The residue ischromatographed on silica H using a DCM/MeOH mixture (100/1; v/v) as theeluent to give 4 g of the expected product.

B) 4-Benzoyl-2-(3,4-dichlorophenyl)-2-(2-hydroxyethyl)morpholine

A mixture of 4 g of the compound obtained in the previous step and 0.7 gof lithium hydroxide monohydrate in 50 ml of MeOH is stirred for 30minutes at RT. The reaction mixture is concentrated under vacuum, theresidue is extracted with ether, the organic phase is washed with waterand dried over MgSO₄ and the solvent is evaporated off under vacuum togive 3.1 g of the expected product.

This compound is also prepared by the procedure described in step A ofEXAMPLE 17.

C)4-Benzoyl-2-(3,4-dichlorophenyl)-2-[2-(methanesulfonyloxy)ethyl]morpholine

1.07 g of methanesulfonyl chloride are added dropwise at RT to asolution of 3.1 g of the compound obtained in the previous step and 0.95g of triethylamine in 50 ml of DCM and the reaction mixture is stirredfor 1 hour at RT. It is concentrated under vacuum, the residue isextracted with an AcOEt/ether mixture (50/50; v/v), the organic phase iswashed with water and dried over MgSO₄ and the solvent is evaporated offunder vacuum to give 3.7 g of the expected product, which is used assuch.

This compound is also prepared by the procedure described in step B ofEXAMPLE 17.

D)4-Benzoyl-2-(3,4-dichlorophenyl)-2-[2-[4-(morpholin-4-ylcarbonylamino)-4-phenylpiperid-1-yl]ethyl]morpholinehydrochloride monohydrate

A mixture of 1.3 g of the compound obtained in the previous step, 1.5 gof 4-(morpholin-4-ylcarbonylamino)-4-phenylpiperidine p-toluenesulfonateand 1.2 g of K₂ CO₃ in 3 ml of DMF is heated at 100° C. for 3 hours.After cooling to RT, the reaction mixture is poured into water and theprecipitate formed is wrung and dried under vacuum. The precipitate ischromatographed on silica H using a DCM/MeOH mixture (from 100/2; v/v to100/3; v/v) as the eluent. The product obtained is dissolved in theminimum amount of DCM, acidified to pH 1 by the addition of a saturatedsolution of gaseous HCl in ether and concentrated under vacuum to give0.13 g of the expected product after crystallization from iso ether.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 1.8 to 4.0 ppm: u: 26H 6.5ppm: s: 1H 6.9 to 7.8 ppm: u: 13H 10.65 ppm: s 1H

EXAMPLE 444-Benzoyl-2-(3,4-dichlorophenyl)-2-[2-[4-phenyl-4-(pyrrolidin-1-ylaminocarbonyl)piperid-1-yl]ethyl]morpholinedihydrochloride dihydrate

A mixture of 1.3 g of the compound obtained in step C of EXAMPLE 43,1.46 g of 4-phenyl-4-(pyrrolidin-1-ylaminocarbonyl)piperidinebenzenesulfonate and 1.17 g of K₂ CO₃ in 5 ml of acetonitrile and 5 mlof DMF is heated at 100° C. for 4 hours. After cooling to RT, thereaction mixture is poured into water and extracted with AcOEt, theorganic phase is washed twice with water and with saturated NaClsolution and dried over MgSO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica H using DCM and then aDCM/MeOH mixture (97/3; v/v) as the eluent. The product obtained isdissolved in acetone, a saturated solution of hydrochloric acid in etheris added until the pH is 1, and the precipitate formed is wrung to give1.01 g of the expected product. M.p.=170-174° C.

EXAMPLE 454-Benzoyl-2-(3,4-difluorophenyl)-2-[2-[4-(methoxycarbonylamino)-4-phenylpiperid-1-yl]ethyl]morpholinehydrochloride monohydrate, (+) isomer

A mixture of 1.2 g of the compound obtained in step C of EXAMPLE 37, 1.3g of 4-(methoxycarbonylamino)-4-phenylpiperidine p-toluenesulfonate and1.2 g of K₂ CO₃ in 3 ml of DMF is heated at 80-100° C. for 2 hours.After cooling to RT, the reaction mixture is poured into water and theprecipitate formed is wrung and dried under vacuum. The precipitate ischromatographed on silica H using a DCM/MeOH mixture (from 100/1.5; v/vto 100/3; v/v) as the eluent. The product obtained is dissolved in DCM,a saturated solution of hydrochloric acid in ether is added until the pHis 1, and the precipitate formed is wrung to give 0.8 g of the expectedproduct. M.p.=170° C.

[α]_(D) ²⁰ =+26.7° (c=1; MeOH)

EXAMPLE 464-Benzoyl-2-(3,4-difluorophenyl)-2-[2-[4-phenyl-4-(pyrrolidin-1-ylcarbonylamino)piperid-1-yl]ethyl]morpholinehydrochloride monohydrate, (+) isomer

This compound is prepared by the procedure described in EXAMPLE 45 from1.2 g of the compound obtained in step C of EXAMPLE 37, 1.4 g of4-phenyl-4-(pyrrolidin-1-ylcarbonylamino)piperidine benzenesulfonate,1.2 g of K₂ CO₃ and 2 ml of DMF to give 0.3 g of the expected product.M.p.=163-168° C.

[α]_(D) ²⁰ =+22.8° (c=1; MeOH)

EXAMPLE 474-Benzoyl-2-[2-[4-benzyl-4-(pyrrolidin-1-ylcarbonylamino)piperid-1-yl]ethyl]-2-(3,4-difluorophenyl)morpholinehydrochloride 1.5 hydrate, (+) isomer

This compound is prepared by the procedure described in EXAMPLE 45 from1.2 g of the compound obtained in step C of EXAMPLE 37, 1.5 g of4-benzyl-4-(pyrrolidin-1-ylcarbonylamino)piperidine p-toluenesulfonate,1.2 g of K₂ CO₃ and 3 ml of DMF to give 0.83 g of the expected product.M.p.=140° C.

[α]_(D) ²⁰ =+28.4° (c=1; MeOH)

EXAMPLE 484-Benzoyl-2-(3,4-difluorophenyl)-2-[2-[4-[2-(dimethylamino)thiazol-4-yl]-4-phenylpiperid-1-yl]ethyl]morpholinedihydrochloride hemihydrate, (+) isomer

This compound is prepared by the procedure described in EXAMPLE 45 from1.2 g of the compound obtained in step C of EXAMPLE 37, 1.55 g of4-[2-(dimethylamino)thiazol-4-yl]-4-phenylpiperidine p-toluenesulfonate,1.2 g of K₂ CO₃ and 3 ml of DMF to give 0.7 g of the expected product.M.p.=147° C.

[α]_(D) ²⁰ =+20.3° (c=1; MeOH)

EXAMPLE 492-[2-[4-(2-Amino-1,3,4-oxadiazol-5-yl)-4-phenylpiperid-1-yl]ethyl]-4-benzoyl-2-(3,4-difluorophenyl)morpholinedihydrochloride, (+) isomer

This compound is prepared by the procedure described in EXAMPLE 45 from1.2 g of the compound obtained in step C of EXAMPLE 37, 1.4 g of4-(2-amino-1,3,4-oxadiazol-5-yl)-4-phenylpiperidine p-toluenesulfonate,1.2 g of K₂ CO₃ and 3 ml of DMF to give 0.6 g of the expected product.M.p.=153° C.

[α]_(D) ²⁰ =+27.2° (c=1; MeOH)

EXAMPLE 505-(3,4-Difluorophenyl)-5-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-onechloride monohydrate, (-) isomer

A)5-[2-(Benzoyloxy)ethyl]-5-(3,4-difluorophenyl)-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one,(-) isomer

1.2 g of potassium tert-butylate are added at RT to a solution of 3.5 gof the compound obtained in Preparation 1.20 ((-) isomer) in a mixtureof 50 ml of THF and 10 ml of DMF and the mixture is stirred for 30minutes at RT. 2.7 g of 3,5-bis(trifluoromethyl)benzyl chloride are thenadded and the reaction mixture is heated at 60° C. for 6 hours. It ispoured into 200 ml of a buffer of pH 2 and extracted with ether, theorganic phase is washed with water and dried over MgSO₄ and the solventis evaporated off under vacuum. The residue is chromatographed on silicaH using DCM as the eluent to give 3.6 g of the expected product.

B)5-(3,4-Difluorophenyl)-5-(2-hydroxyethyl)-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one,(-) isomer

A mixture of 3.6 g of the compound obtained in the previous step and0.32 g of lithium hydroxide monohydrate in 50 ml of MeOH and 5 ml ofwater is stirred for 2 hours at RT. The reaction mixture is concentratedunder vacuum, the residue is taken up with water and extracted withether, the organic phase is washed twice with water and dried over MgSO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H using DCM and then a DCM/MeOH mixture (98/2;v/v) as the eluent to give 2.6 g of the expected product.

C)5-(3,4-Difluorophenyl)-5-[2-(methanesulfonyloxy)ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one,(-) isomer

A solution of 2.6 g of the compound obtained in the previous step in 50ml of DCM is cooled to 0° C., 1.14 ml of triethylamine and then 0.62 mlof methanesulfonyl chloride are added and the reaction mixture isstirred for 10 minutes. It is concentrated under vacuum, the residue isextracted with ether, the organic phase is washed twice with water anddried over MgSO₄ and the solvent is evaporated off under vacuum to give3 g of the expected product, which is used as such.

D)5-(3,4-Difluorophenyl)-5-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-onechloride monohydrate, (-) isomer

A mixture of 2 g of the compound obtained in the previous step and 1 gof 4-phenyl-1-azabicyclo[2.2.2]octane in 1 ml of DMF is heated at 90° C.for 2 hours. After cooling to RT, the reaction mixture is poured into 1N HCl solution and extracted with DCM, the organic phase is washed with1 N HCl solution and with saturated NaCl solution and dried over MgSO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H using DCM and then a DCM/MeOH mixture(90/10; v/v) as the eluent to give 1.45 g of the expected product aftercrystallization from iso ether. M.p.=130° C. (dec.).

[α]_(D) ²⁰ =-36.2° (c=1; MeOH)

EXAMPLE 514-Benzoyl-2-(3,4-difluorophenyl)-2-[2-[4-(N',N'-dimethylureido)-4-phenylpiperid-1-yl]ethyl]morpholinefumarate

A) 4-Benzoyl-2-(3,4-difluorophenyl)-2-(formylmethyl)morpholine

A solution of 0.32 ml of oxalyl chloride in 7.3 ml of DCM is cooled to-78° C. under a nitrogen atmosphere and a solution of 0.51 ml of DMSO in3.5 ml of DCM is added dropwise, followed by a solution of 1 g of thecompound obtained in step A of EXAMPLE 27 in 7.5 ml of DCM and 0.7 ml ofDMSO. The reaction mixture is stirred for 30 minutes at -60° C., 2 ml oftriethylamine are then added and the reaction mixture is stirred whilethe temperature is allowed to rise to RT. It is washed with 1 N HClsolution, with saturated Na₂ CO₃ solution and with water, the organicphase is dried over MgSO₄ and the solvent is evaporated off under vacuumto give 1.03 g of the expected product in the form of an oil.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.7 to 4.8 ppm: u: 8H 7.0to 8.0 ppm: u: 8H 9.6 ppm: s: 1H

B)4-Benzoyl-2-(3,4-difluorophenyl)-2-[2-[4-(N',N'-dimethylureido)-4-phenylpiperid-1-yl]ethyl]morpholinefumarate

A solution of 1 g of the compound obtained in the previous step in 10 mlof MeOH is added at RT to a solution of 0.72 g of4-(N',N'-dimethylureido)-4-phenylpiperidine (free base) and 0.16 ml ofacetic acid in 10 ml of MeOH and the mixture is stirred for 5 minutes atRT. A solution of 0.19 g of sodium cyanoborohydride in 10 ml of MeOH isthen added all at once and the reaction mixture is stirred for 4 hoursat RT. It is neutralized by the addition of 10% Na₂ CO₃ solution andextracted with DCM, the organic phase is dried over MgSO₄ and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica H using DCM and then a DCM/MeOH mixture (96/4; v/v) as theeluent. The product obtained (1.1 g) is dissolved in 20 ml of acetone,0.24 g of fumaric acid is added and the mixture is stirred for 1 hour atRT. The crystalline product formed is wrung and washed with acetone andthen with ether to give 1.35 g of the expected product. M.p.=204° C.

The compounds according to the invention which are collated in TABLE Ibelow are prepared by the procedure described in EXAMPLE 34 from thecompound obtained in step B of EXAMPLE 14 and the piperidines describedin the Preparations.

                                      TABLE I                                     __________________________________________________________________________                                                (I)                                                                           1  STR91##                           -                                                                                                             Salt, solvate;                                  M.p. ° C. or NMR;                                                   Example Am Ar.sub.1 recrystallization solvent                               __________________________________________________________________________      52                                                                                                             2  STR92##                                                                    3  HCl, 2.5 H.sub.2 O 138-140 pentane/e                                       ther                                          - 53                                                                                                          4  STR94##                                                                    3  HCl, 2 H.sub.2 O 128 (dec) pentane/e                                       ther                                          - 54                                                                                                          5  STR96##                                                                    3  HCl, 2.5 H.sub.2 O 138-140 pentane/e                                       ther                                          - 55                                                                                                          6  STR98##                                                                    3  2 HCl, 2 H.sub.2 O  198 (dec)                                              pentane/iso ether                             - 56                                                                                                          7  STR100##                                                                   3  HCl, 1 H.sub.2 O 130-134 pentane                                             - 57                                                                        8  STR102##                                                                   3  HCl, 1 H.sub.2 O NMR penatne/ether                                           - 58                                                                        9  STR104##                                                                   3  HCl, 0.5 H.sub.2 O NMR DCM/ether                                             - 59                                                                        0  STR106##                                                                   3  HCl, 1 H.sub.2 O NMR DCM/ether                                               - 60                                                                        1  STR108##                                                                   3  HCl, 1 H.sub.2 O 148 DCM/pentane                                             - 61                                                                        2  STR110##                                                                   3  HCl, 1.5 H.sub.2 O 158 pentane/ether       - 62                                                                                                          3  STR112##                                                                   3  2 HCl, 1.5 H.sub.2 O 140-145            __________________________________________________________________________                                       ether                                  

Proton NMR spectrum of EXAMPLE 57 at 200 MHz in DMSO-d₆ δ: 1.6 to 3.7ppm: u: 17 H 3.75 to 4.8 ppm: u: 6 H 7.0 to 7.6 ppm: u: 13 H 10.2 to 11ppm: 2s: 1 H

Proton NMR spectrum of EXAMPLE 58 at 200 MHz in DMSO-d₆ δ: 0.8 to 4.9ppm: u: 30 H 7.0 to 7.8 ppm: u: 13 H 10.0 ppm: s: 1 H

Proton NMR spectrum of EXAMPLE 59 at 200 MHz in DMSO-d₆ δ: 1.1 to 3.8ppm: u: 24 H 3.9 to 4.75 ppm: u: 4 H 6.9 to 7.7 ppm: u: 13 H 9.7 ppm: s:1 H

EXAMPLE 636-[2-[4-Benzyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-6-(3,4-difluorophenyl)-4-[3,5-bis(trifluoromethyl)benzyl]morpholin-3-onechloride dihydrate

A mixture of 0.86 g of the compound obtained in step C of EXAMPLE 26 and0.47 g of 4-benzyl-1-azabicyclo[2.2.2]octane (or 4-benzylquinuclidine)in 1 ml of DMF is heated at 90° C. for 9 hours. After cooling to RT, thereaction mixture is poured into water and extracted with DCM, theorganic phase is washed twice with 2 N HCl solution and twice withsaturated NaCl solution and dried over Na₂ SO₄ and the solvent isevaporated off under vacuum. The residue is chromatographed on silica Husing DCM and then a DCM/MeOH mixture (90/10; v/v) as the eluent to give0.4 g of the expected product after crystallization from ether.M.p.=135° C. (dec.).

EXAMPLE 646-(3,4-Difluorophenyl)-4-[3,5-bis(trifluoromethyl)benzyl]-6-[2-[4-(piperid-1-yl)piperid-1-yl]ethyl]morpholin-3-onedihydrochloride hemihydrate

A mixture of 0.86 g of the compound obtained in step C of EXAMPLE 26 and0.7 g of 4-(piperid-1-yl)piperidine in 3 ml of DMF is heated at 70° C.for 4 hours 30 minutes. After cooling to RT, the reaction mixture ispoured into water and extracted with AcOEt, the organic phase is washedwith 1 N NaOH solution and with saturated NaCl solution and dried overNa₂ SO₄ and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H using DCM and then a DCM/MeOH mixture(90/10; v/v) as the eluent. The product obtained is taken up with asaturated solution of hydrochloric acid in ether and the precipitateformed is wrung to give 0.49 g of the expected product. M.p.=260° C.(dec.).

The compounds according to the invention which are collated in TABLE IIbelow are prepared by the procedures described in the precedingEXAMPLES.

                                      TABLE II                                    __________________________________________________________________________                                              (I)                                                                           8  STR114##                            -                                                                                                           Salt, solvate;                                    M.p. ° C. or NMR;                                                   Example Am Ar.sub.1 recrystallization solvent                               __________________________________________________________________________      65 (a)                                                                                                       4  STR115##                                                                   3  2 HCl, 1 H.sub.2 O NMR                       - 66 (b)                                                                                                    5  STR117##                                                                   6  HCl, 1.5 H.sub.2 O 192-195 DCM/ether                                         - 67 (c)                                                                    7  STR119##                                                                   6  HCl, 1 H.sub.2 O NMR ether                __________________________________________________________________________     (a) This compound is prepared by the procedure described in EXAMPLE 44        from the compound obtained in step C of EXAMPLE 43 and the compound           obtained in Preparation 2.16, in the form of the free base.                   (b) This compound is prepared by the procedure described in step B of         EXAMPLE 51 from the compound obtained in step A of EXAMPLE 51 and the         compound obtained in Preparation 2.17 (free base). After chromatography,      the product obtained is dissolved in DCM, a saturated solution of             hydrochloric acid in ether is added until the pH is 1, and the expected       hydrochloride is wrung.                                                       (c) This compound is prepared by the procedure described in step B of         EXAMPLE 51 from the compound obtained in step A of EXAMPLE 51 and the         compound obtained in Preparation 2.18 (free base). After chromatography,      the product obtained is taken up with a saturation solution of                hydrochloric acid in ether and the expected hydrochloride is wrung.      

Proton NMR spectrum of EXAMPLE 65 at 200 MHz in DMSO-d₆ δ: 0.8 to 4.2ppm: u: 28H; 7.0 to 7.8 ppm: u: 8H; 7.9 to 8.6 ppm: 2s: 2H; 10.4 to 11.6ppm: u: 2H.

Proton NMR spectrum of EXAMPLE 67 at 200 MHz in DMSO-d₆ δ: 2.0 to 4.2ppm: u: 21 H 5.9 ppm: mt: 1 H 6.75 ppm s: 1 H 7.0 to 7.8 ppm: u: 8 H10.95 ppm: s: 1 H.

EXAMPLE 684-Benzoyl-2-(3,4-difluorophenyl)-2-[2-(4-phenyl-4-ureidopiperid-1-yl)ethyl]morpholinehydrochloride dihydrate, (+) isomer

A) 4-Benzoyl-2-(3,4-difluorophenyl)-2-(formylmethyl)morpholine, (+)isomer

A solution of 2.6 ml of oxalyl chloride in 59 ml of DCM is cooled to-78° C. under a nitrogen atmosphere and a solution of 4.6 ml of DMSO in29.5 ml of DCM is added dropwise, followed by a solution of 8.2 g of thecompound obtained in step B of EXAMPLE 37 in 59 ml of DCM and 5.7 ml ofDMSO. The reaction mixture is stirred for 30 minutes at -60° C., 16 mlof triethylamine are then added and the reaction mixture is stirredwhile the temperature is allowed to rise to RT. It is washed with 1 NHCl solution, with water, with saturated NaHCO₃ solution and with water,the organic phase is dried over MgSO₄ and the solvent is evaporated offunder vacuum to give 7.5 g of the expected product in the form of anoil.

B)4-Benzoyl-2-(3,4-difluorophenyl)-2-[2-(4-phenyl-4-ureidopiperid-1-yl)ethyl]morpholinehydrochloride dihydrate, (+) isomer

A solution of 2.5 g of the compound obtained in the previous step in 26ml of MeOH is added at RT to a solution of 1.6 g of4-phenyl-4-ureidopiperidine (free base) and 0.4 ml of acetic acid in 26ml of MeOH and the mixture is stirred for 5 minutes at RT. A solution of0.5 g of sodium cyanoborohydride in 26 ml of MeOH is then added all atonce and the reaction mixture is stirred for 4 hours at RT. It is pouredinto 200 ml of 10% Na₂ CO₃ solution and extracted with AcOEt, theorganic phase is washed with water and dried over MgSO₄ and the solventis evaporated off under vacuum. The residue is chromatographed on silicaH using a gradient of a DCM/MeOH mixture (from 100/5; v/v to 100/7.5;v/v) as the eluent. The product obtained is dissolved in DCM, asaturated solution of hydrochloric acid in ether is added until the pHis 1, and the precipitate formed is wrung to give 1.6 g of the expectedproduct. M.p.=187-190° C.

[α]_(D) ²⁰ =+22.5° (c=1; MeOH)

EXAMPLE 694-Benzoyl-2-(3,4-difluorophenyl)-2-[2-[4-(N'-methylureido)-4-phenylpiperid-1-yl]ethyl]morpholinehydrochloride monohydrate, (+) isomer

This compound is prepared by the procedure described in step B ofEXAMPLE 68 from 1.85 g of 4-(N'-methylureido)-4-phenylpiperidine (freebase), 0.44 ml of acetic acid and 26 ml of MeOH, and then 2.75 g of thecompound obtained in step A of EXAMPLE 68 in 26 ml of MeOH and 0.55 g ofsodium cyanoborohydride in 26 ml of MeOH. This gives 2 g of the expectedproduct. M.p.=170-173° C.

[α]_(D) ²⁰ =+23.4° (c=1; MeOH)

EXAMPLE 704-Benzoyl-2-(3,4-difluorophenyl)-2-[2-[4-(3,3-dimethylcarbazoyl)-4-phenylpiperid-1-yl]ethyl]morpholinedihydrochloride 1.5 hydrate, (+) isomer

This compound is prepared by the procedure described in step B ofEXAMPLE 68 from 1.55 g of 4-(3,3-dimethylcarbazoyl)-4-phenylpiperidine(free base) and 0.38 ml of acetic acid in 26 ml of MeOH, and then 2.4 gof the compound obtained in step A of EXAMPLE 68 in 26 ml of MeOH and0.47 g of sodium cyanoborohydride in 26 ml of MeOH. This gives 1.82 g ofthe expected product.

[α]_(D) ²⁰ =+22.5° (c=1; MeOH)

EXAMPLE 712-(3,4-Difluorophenyl)-4-[2-(3-isopropoxyphenyl)acetyl]-2-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]morpholinechloride monohydrate

A)2-[2-(Benzoyloxy)ethyl]-2-(3,4-difluorophenyl)-4-[2-(3-isopropoxyphenyl)acetyl]morpholine

3.2 g of BOP are added at RT to a solution of 2.1 g of the compoundobtained in Preparation 1.21, 1.2 g of 2-(3-isopropoxyphenyl)acetic acidand 2.2 ml of triethylamine in 50 ml of DCM and the reaction mixture isstirred for 15 minutes at RT. It is concentrated under vacuum, theresidue is extracted with ether, the organic phase is washed with 1 NHCl solution, with water and with 10% Na₂ CO₃ solution and dried overMgSO₄ and the solvent is evaporated off under vacuum to give 3.2 g ofthe expected product in the form of an oil.

B)2-(3,4-Difluorophenyl)-2-(2-hydroxyethyl)-4-[2-(3-isopropoxyphenyl)acetyl]morpholine

A mixture of 3.2 g of the compound obtained in the previous step, 2 mlof concentrated NaOH solution and 50 ml of MeOH is stirred for 2 hoursat RT. It is concentrated under vacuum, the residue is extracted withether, the organic phase is washed twice with water and dried over MgSO₄and the solvent is evaporated off under vacuum to give 2.3 g of theexpected product in the form of an oil.

C)2-(3,4-Difluorophenyl)-4-[2-(3-isopropoxyphenyl)acetyl]-2-[2-(methanesulfonyloxy)ethyl]morpholine

0.93 ml of triethylamine and then 0.51 ml of methanesulfonyl chlorideare added to a solution of 2.3 g of the compound obtained in theprevious step in 50 ml of DCM and the mixture is stirred for 15 minutesat RT. It is concentrated under vacuum, the residue is extracted withether, the organic phase is washed with water and with 10% Na₂ CO₃solution and dried over MgSO₄ and the solvent is evaporated off undervacuum to give 2.7 g of the expected product in the form of an oil.

D)2-(3,4-Difluorophenyl)-4-[2-(3-isopropoxyphenyl)acetyl]-2-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]morpholinechloride monohydrate

A mixture of 1.3 g of the compound obtained in the previous step and0.72 g of 4-phenyl-1-azabicyclo[2.2.2]octane in 1.5 ml of DMF is heatedat 90° C. for 5 hours. After cooling to RT, the reaction mixture ispoured into 1 N HCl solution and extracted with DCM, the organic phaseis washed with 1 N HCl solution and with saturated NaCl solution anddried over MgSO₄ and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica H using DCM and then a DCM/MeOHmixture (90/10; v/v) as the eluent to give 0.38 g of the expectedproduct after crystallization from iso ether. M.p.=136° C. (dec.).

EXAMPLE 722-(3,4-Difluorophenyl)-4-[2-(3-isopropoxyphenyl)acetyl]-2-[2-[4-(piperid-1-yl)piperid-1-yl]ethyl]morpholinedihydrochloride hemihydrate

A mixture of 1.3 g of the compound obtained in step C of EXAMPLE 71 and1.1 g of 4-(piperid-1-yl)piperidine in 4 ml of DMF is heated at 70° C.for 4 hours. After cooling to RT, the reaction mixture is poured intoiced water and extracted with AcOEt, the organic phase is washed with 1N NaOH solution and with saturated NaCl solution and dried over Na₂ SO₄and the solvent is evaporated off under vacuum. The residue ischromatographed on silica H using DCM and then a DCM/MeOH mixture(90/10; v/v) as the eluent. The product obtained is taken up with asaturated solution of hydrochloric acid in ether and the precipitateformed is wrung to give 0.49 g of the expected product. M.p.=270° C.(dec.).

EXAMPLE 732-(3,4-Difluorophenyl)-2-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-4-[3,5-bis(trifluoromethyl)benzoyl]morpholinechloride 1.5 hydrate

A)2-[2-(Benzoyloxy)ethyl]-2-(3,4-difluorophenyl)-4-[3,5-bis(trifluoromethyl)benzoyl]morpholine

A solution of 2.1 g of the compound obtained in Preparation 1.21 and 1ml of triethylamine in 50 ml of DCM is cooled to 0° C., 1.24 ml of3,5-bis(trifluoromethyl)benzoyl chloride are added dropwise and thereaction mixture is stirred for 5 minutes. It is washed twice withwater, the organic phase is dried over MgSO₄ and the solvent isevaporated off under vacuum to give 3.5 g of the expected product in theform of an oil.

B)2-(3,4-Difluorophenyl)-2-(2-hydroxyethyl)-4-[3,5-bis(trifluoromethyl)benzoyl]morpholine

A mixture of 3.5 g of the compound obtained in the previous step, 2 mlof concentrated NaOH solution and 50 ml of MeOH is stirred for 2 hoursat RT. It is concentrated under vacuum, the residue is extracted withether, the organic phase is washed twice with water and dried over MgSO₄and the solvent is evaporated off under vacuum to give 0.84 g of theexpected product after crystallization from an iso ether/pentanemixture. M.p.=101° C.

C)2-(3,4-Difluorophenyl)-2-[2-(methanesulfonyloxy)ethyl]-4-[3,5-bis(trifluoromethyl)benzoyl]morpholine

0.5 ml of triethylamine is added to a solution of 0.84 g of the compoundobtained in the previous step in 10 ml of DCM, the mixture is cooled to0° C., 0.26 ml of methanesulfonyl chloride is then added and thereaction mixture is stirred for 5 minutes at RT. It is washed twice withwater, the organic phase is dried over MgSO₄ and the solvent isevaporated off under vacuum to give 0.98 g of the expected product.

D)2-(3,4-Difluorophenyl)-2-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-4-[3,5-bis(trifluoromethyl)benzoyl]morpholinechloride 1.5 hydrate

A mixture of 0.98 g of the compound obtained in the previous step and0.65 g of 4-phenyl-1-azabicyclo[2.2.2]octane in 1 ml of DMF is heated at100° C. for 3 hours. After cooling to RT, the reaction mixture is pouredinto 1 N HCl solution and extracted with DCM, the organic phase iswashed with 1 N HCl solution and with saturated NaCl solution and driedover MgSO₄ and the solvent is evaporated off under vacuum. The residueis chromatographed on silica H using DCM and then a DCM/MeOH mixture(90/10; v/v) as the eluent to give 0.42 g of the expected product aftercrystallization from iso ether. M.p.=170° C. (dec.).

EXAMPLE 745-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-3-benzoyl-5-(3,4-dichlorophenyl)oxazolidinehydrochloride monohydrate

A) 3-Benzoyl-5-(3,4-dichlorophenyl)-5-(2-hydroxyethyl)oxazolidine

A solution of 1.23 g of benzoyl chloride in 10 ml of DCM is addeddropwise at RT to a solution of 3.2 g of the compound obtained inPreparation 1.22 and 1 g of triethylamine in 50 ml of DCM and themixture is stirred for 1 hour at RT. A further 1.76 g of triethylamineand then 2.46 g of benzoyl chloride are added and the mixture is stirredfor 1 hour at RT. It is concentrated under vacuum, the residue is takenup with water and extracted with AcOEt, the organic phase is washed witha buffer solution of pH 2 and with saturated NaCl solution and driedover Na₂ SO₄ and the solvent is evaporated off under vacuum. The residueis taken up with 30 ml of MeOH, 2 ml of 30% NaOH solution are added andthe mixture is stirred for 30 minutes at RT. It is concentrated undervacuum, the residue is extracted with ether, the organic phase is washedwith water and dried over Na₂ SO₄ and the solvent is evaporated offunder vacuum. The residue is chromatographed on silica H using aDCM/MeOH mixture (100/1.5; v/v) as the eluent to give 1.6 g of theexpected product.

B)3-Benzoyl-5-(3,4-dichlorophenyl)-5-[2-(methanesulfonyloxy)ethyl]oxazolidin

A solution of 0.55 g of methanesulfonyl chloride in 5 ml of DCM is addeddropwise at RT to a solution of 1.6 g of the compound obtained in theprevious step and 0.485 g of triethylamine in 50 ml of DCM and themixture is stirred for 30 minutes at RT. It is concentrated undervacuum, the residue is extracted with AcOEt, the organic phase is washedwith water and dried over Na₂ SO₄ and the solvent is evaporated offunder vacuum to give 1.9 g of the expected product.

C)5-[2-(4-Acetamido-4-phenylpiperid-1-yl)ethyl]-3-benzoyl-5-(3,4-dichlorophenyl)oxazolidinehydrochloride monohydrate

A mixture of 1.8 g of the compound obtained in the previous step, 1.7 gof 4-acetamido-4-phenylpiperidine p-toluenesulfonate and 1.7 g of K₂ CO₃in 4 ml of DMF is heated at 80-100° C. for 2 hours. After cooling to RT,the reaction mixture is poured into water and the precipitate formed iswrung and dried under vacuum. The precipitate is chromatographed onsilica H using a DCM/MeOH mixture (100/3; v/v) as the eluent. Theproduct is dissolved in DCM, a saturated solution of hydrochloric acidin ether is added until the pH is 1, and the precipitate formed is wrungto give 1 g of the expected product. M.p.=165-170° C.

EXAMPLE 755-(3,4-Difluorophenyl)-5-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-onechloride monohydrate, (+) isomer

A)5-[2-(Benzoyloxy)ethyl]-5-(3,4-difluorophenyl)-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one,(+) isomer

This compound is prepared by the procedure described in step A ofEXAMPLE 50 from the compound obtained in Preparation 1.23 ((+) isomer).

B)5-(3,4-Difluorophenyl)-5-(2-hydroxyethyl)-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one,(+) isomer

This compound is prepared by the procedure described in step B ofEXAMPLE 50 from the compound obtained in the previous step.

C)5-(3,4-Difluorophenyl)-5-[2-(methanesulfonyloxy)ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-one,(+) isomer

This compound is prepared by the procedure described in step C ofEXAMPLE 50 from the compound obtained in the previous step.

D)5-(3,4-Difluorophenyl)-5-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]-3-[3,5-bis(trifluoromethyl)benzyl]oxazolidin-2-onechloride monohydrate, (+) isomer

This compound is prepared by the procedure described in step D ofEXAMPLE 50 from the compound obtained in the previous step and4-phenyl-1-azabicyclo[2.2.2]octane.

[α]_(D) ²⁰ =+36.2° (c=1; MeOH)

EXAMPLE 764-Benzoyl-2-[3-[4-carbamoyl-4-(piperid-1-yl)piperid-1-yl]propyl]-2-(3,4-dichlorophenyl)morpholinedihydrochloride

This compound is prepared by the procedure described in step C ofEXAMPLE 19 from the compound obtained in step B of EXAMPLE 19 and thecompound obtained in Preparation 2.16.

EXAMPLE 772-(3,4-Dichlorophenyl)-4-[2-(3-chlorophenyl)acetyl]-2-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]morpholinechloride

A)2-[2-(Benzoyloxy)ethyl]-2-(3,4-dichlorophenyl)-4-[2-(3-chlorophenyl)acetyl]morpholine

This compound is prepared by the procedure described in step A ofEXAMPLE 71 from the compound obtained in Preparation 1.19 and2-(3-chlorophenyl)acetic acid.

B)2-(3,4-Dichlorophenyl)-4-[2-(3-chlorophenyl)acetyl]-2-(2-hydroxyethyl)morpholine

This compound is prepared by the procedure described in step B ofEXAMPLE 71 from the compound obtained in the previous step.

C)2-(3,4-Dichlorophenyl)-4-[2-(3-chlorophenyl)acetyl]-2-[2-(methanesulfonyloxy)ethyl]morpholine

This compound is prepared by the procedure described in step C ofEXAMPLE 71 from the compound obtained in the previous step andmethanesulfonyl chloride.

D)2-(3,4-Dichlorophenyl)-4-[2-(3-chlorophenyl)acetyl]-2-[2-[4-phenyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]morpholinechloride

This compound is prepared by the procedure described in step D ofEXAMPLE 71 from the compound obtained in the previous step and4-phenyl-1-azabicyclo[2.2.2]octane.

Proton NMR spectrum at 200 MHz in DMSO-d₆ δ: 2.0 to 2.5 ppm: u: 8 H;2.55 to 4.6 ppm: u: 16 H; 7.0 to 8.0 ppm: u: 12 H.

EXAMPLE 782-(3,4-Dichlorophenyl)-4-[2-(3-chlorophenyl)acetyl]-2-[4-benzyl-1-azoniabicyclo[2.2.2]oct-1-yl]ethyl]morpholinechloride

This compound is prepared by the procedure described in step D ofEXAMPLE 71 from the compound obtained in step C of EXAMPLE 77 and4-benzyl-1-azabicyclo[2.2.2]octane.

What is claimed is:
 1. A compound of the formula ##STR121## in which: mis 2 or 3;Ar₁ is a phenyl group which is unsubstituted ormonosubstituted or polysubstituted by a substituent which is a halogenatom, a hydroxyl group, a (C₁ -C₄)-alkoxy group, a (C₁ -C₄)-alkyl group,a trifluoromethyl group or a methylenedioxy group, said substituentsbeing identical or different; a thienyl group which is unsubstituted orsubstituted by a halogen atom; a benzothienyl group which isunsubstituted or substituted by a halogen atom; a naphthyl group whichis unsubstituted or substituted by a halogen atom; an indolyl groupwhich is unsubstituted or N-substituted by a (C₁ -C₄)-alkyl group or abenzyl group; an imidazolyl group which is unsubstituted or substitutedby a halogen atom; a pyridyl group which is unsubstituted or substitutedby a halogen atom; or a biphenyl group; and A is divalent radical whichisA₁) --O--CO--, A₂) --CH₂ --O--CO--, A₅) --N(R₁)--CO--, A₆)--N(R₁)--CO--CO--, A₇) --N(R₁)--CH₂ --CH₂ --, A₈) --O--CH₂ -- in whichR₁ is a hydrogen atom or a (C₁ -C₄)-alkyl group; R_(I) is two hydrogenatoms and R_(II) is:either a group --O--E, in which E is a hydrogen atomor an O-protecting group, or a group O--SO₂ --Y, in which Y is a methyl,phenyl, tolyl or trifluoromethyl group; or alternatively R_(I) is anoxygen atom and R_(II) is a hydrogen atom; and T^(I) is --CH₂ --Z;--CH(C₆ H₅)₂, --C(C₆ H₅)₃ ; T^(I) may also be a group --CO--B--Z if A isa divalent group which is --N(R₁)--CH₂ --CH₂ --, or --O--CH₂ --; orT^(I) may also be hydrogen if R_(I) is two hydrogen atoms and R_(II) issimultaneously a group --O--E; Z is an optionally substituted mono-, di-or tri-cyclic aromatic or hetero-aromatic group; and B is a direct bondor a methylene group, in enantiomerically pure form or in racemic form.